# gene_set_details

systematic_name: M41128
exact_source: Suppl Table 1A, Tab DEGs_TIV
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-2.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 7d vs 0d in adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D. Comment: Supplementary Table 1a: All the differentially expressed genes identified in PBMCs of TIV vaccinees.

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41129
exact_source: Suppl Table 1A, Tab DEGs_TIV
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-2.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 7d vs 0d in adults (18-50) after exposure to FluMist , time point 7D. Comment: Supplementary Table 1a: All the differentially expressed genes identified in PBMCs of TIV vaccinees.

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41130
exact_source: Supplementary Table 2a: LAIV-mDC
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in myeloid dendritic cell 7d vs 0d in young adults (18-50) after exposure to FluMist , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41131
exact_source: Suppl Table 1B, Tab DEGs_LAIV
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-2.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 7d vs 0d in adults (18-50) after exposure to FluMist , time point 7D. Comment: Supplementary Table 1b: All the differentially expressed genes identified in PBMCs of TIV vaccinees.

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41132
exact_source: Fig 7B
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072604/figure/ppat.1005892.g007/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes negatively correlated with peak T cell response 28d in peripheral blood mononuclear cell in seniors (50-75) after exposure to Zostavax, time point 14D. Comment: negative correlation coefficients between gene expression level at day 14 after vaccination and peak to day 28 T cell responses

description_full:
[cell repeats an earlier one in this file: 1196 characters]


systematic_name: M41133
exact_source: Fig 4 & Suppl Table 4
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049462/bin/NIHMS593578-supplement-01.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes that are components of a model predictive of response in peripheral blood mononuclear cell 3d vs 0d in adults (18-45) after exposure to YF-17D vaccine , time point 3D. Comment: Suppl Table 4: genes validated by ClaNC as being predictive of CD8+ T cell responses from Fig. 4.

description_full:
[cell repeats an earlier one in this file: 893 characters]


systematic_name: M41134
exact_source: Abstract
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 6d/7d vs 0d in children (3-17) after exposure to Fluenz (LAIV) , time point 6D and 7D combined (identical signature) , administered i.n.

description_full:
  Live attenuated influenza vaccines (LAIV) can prevent influenza illness and death in children. The absence of known correlates of protection induced by LAIV requires human studies of underlying mechanisms of vaccine-induced immunity, to further elucidate the immunological processes occurring. In this study, children scheduled for elective tonsillectomy were enrolled in a clinical trial to evaluate the immune response to LAIV, in order to compare T and B cell gene expression profiles. Twenty-three children (aged 3-17 years) were divided into 4 groups; unvaccinated controls, or vaccinated intranasally with LAIV at days 3-4, 6-7, and 12-15 before tonsillectomy. Total RNA extraction was performed on tonsillar tissue and high RNA quality was assured. The samples were then analyzed using a validated RT2 Profiler PCR Array containing 84 gene-specific primers involved in B and T cell activation, proliferation, differentiation, regulation and polarization. The gene expression after LAIV vaccination was subsequently compared to the controls. We observed that at d 3-4 post vaccination, 6 genes were down-regulated, namely APC, CD3G, FASLG, IL7, CD8A and TLR1. Meanwhile at 6-7 days post vaccination, 9 genes were significantly up-regulated, including RIPK2, TGFB1, MICB, SOCS1, IL2RA, MS4A1, PTPRC, IL2 and IL8. By days 12-15 the genes RIPK2, IL4, IL12B and TLR2 were overexpressed. RIPK2 was upregulated at all 3 time points. Our data suggests an overall proliferation, differentiation and regulation of B and T cells in the tonsils following LAIV, where the majority of genes were up-regulated at days 6-7 and normalized by days 12-15. These findings may provide a first step into defining future biomarkers or correlates of protection after LAIV immunization.


systematic_name: M41135
exact_source: Suppl Table 2
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834766/bin/Table_2.XLSX
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 1d vs 0hr in adults (18-45) after exposure to CN54gp140 adjuvanted with GLA-AF , time point 1D , administered i.m.

description_full:
[cell repeats an earlier one in this file: 2100 characters]


systematic_name: M41136
exact_source: Suppl Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067885/bin/khvi-14-07-1450122-s001.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell non-responders vs responders in adults (<50) after exposure to Heptatitis B surface antigen vaccine (HBsAg) , time point 28D

description_full:
[cell repeats an earlier one in this file: 1976 characters]


systematic_name: M41137
exact_source: Suppl. Fig 8
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485475/bin/NIHMS65741-supplement-1.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell -7d vs 1d in adults (18-64) (medium/high AE subjects) after exposure to Pandemrix (A/California/7/09 (H1N1)) , time point 1D

description_full:
[cell repeats an earlier one in this file: 858 characters]


systematic_name: M41138
exact_source: Table III, see also Suppl Table III
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 2m vs 0m in young adults (18-25) after exposure to HPV-16 L1 VLP , time point 2M. Comment: List of DE Genes After Vaccination Using p<0.05 as Cutoff

description_full:
[cell repeats an earlier one in this file: 1766 characters]

external_details_URL:
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701477/table/T3/| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701477/bin/NIHMS83712-supplement-Supplemetary_t.doc


systematic_name: M41139
exact_source: Suppl mat, 2016HV0244R-s01.xlsx
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287313/bin/khvi-13-01-1227900-s001.zip
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood vaccinated vs control in adults (23-48) after exposure to Live attenuated vaccine TC-83 , time point 2D

description_full:
[cell repeats an earlier one in this file: 1747 characters]


systematic_name: M41140
exact_source: Supplemental Document 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605227/bin/jem.20082292_1.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 7d vs 0d in unknown after exposure to YF-Vax/Stamaril , time point 7D

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41141
exact_source: Supplemental Document 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605227/bin/jem.20082292_1.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 10d vs 0d in unknown after exposure to YF-Vax/Stamaril , time point 10D

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41142
exact_source: Supplemental Document 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605227/bin/jem.20082292_1.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 3d vs 0d in unknown after exposure to YF-Vax/Stamaril , time point 3D

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41143
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in B cell 3d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 3D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41144
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in natural killer cell 3d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 3D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41145
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in myeloid dendritic cell 7d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 7D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41146
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 7d vs 0d in adults after exposure to Inactivated influenza vaccine , time point 7D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41147
exact_source: Supplemental Document 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605227/bin/jem.20082292_1.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 3d vs 0d in unknown after exposure to YF-Vax/Stamaril , time point 3D

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41148
exact_source: Suppl mat, 2016HV0244R-s01.xlsx
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287313/bin/khvi-13-01-1227900-s001.zip
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in blood vaccinated vs control in adults (23-48) after exposure to Live attenuated vaccine TC-83 , time point 14D

description_full:
[cell repeats an earlier one in this file: 1747 characters]


systematic_name: M41149
exact_source: Suppl Table 1A, Tab DEGs_TIV
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-2.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 3d vs 0d in adults (18-50) after exposure to Fluarix/Fluvirin , time point 3D. Comment: Supplementary Table 1a: All the differentially expressed genes identified in PBMCs of TIV vaccinees.

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41150
exact_source: Fig 5b
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946932/figure/F5/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 3d vs 0d in adults (18-45) after exposure to Menomune A/C/Y/W-135 , time point 3D

description_full:
[cell repeats an earlier one in this file: 1137 characters]


systematic_name: M41151
exact_source: Suppl Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092249/bin/supp_jiu079_jiu079supp_table1.doc
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 1d vs 0d in children (0.5-14y) after exposure to Fluzone , time point 1D. Comment: ~80% of cohort were white, ~50/50 Female:male

description_full:
[cell repeats an earlier one in this file: 1344 characters]


systematic_name: M41153
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in myeloid dendritic cell 1d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 1D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41154
exact_source: Suppl Fig 1D
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520794/bin/NIHMS880612-supplement-Supp_Fig_1.tiff
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes positively correlated with memory B cell response at 28d in peripheral blood mononuclear cell in seniors (50-74) after exposure to Fluarix , time point 28D. Comment: D: Late gene expression individual gene models (predicting peak B cell ELISPOT response) for module 11 (D, MSE=2.062)

description_full:
[cell repeats an earlier one in this file: 1537 characters]


systematic_name: M41155
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 6hr/1DY vs 0hr in adults (18-45) (low IgM responders) after exposure to CN54gp140 adjuvanted with GLA-AF , time point 6H/1DY combined (identical signature) , administered i.m.

description_full:
[cell repeats an earlier one in this file: 2100 characters]

exact_source:
  Results: Early BTM Signatures Induced in Whole Blood Post Vaccination Correlate with Later Serum Antibody Responses


systematic_name: M41156
exact_source: Suppl Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946173/bin/mmc1.docx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell responders vs nonresponders in adults (55-64) after exposure to Fluarix , time point 0D. Comment: Gene expression related to HAI response

description_full:
[cell repeats an earlier one in this file: 1414 characters]


systematic_name: M41157
exact_source: Suppl Table IV
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701477/bin/NIHMS83712-supplement-Suplementary_t.doc
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell stimulated vs unstimulated in young adults (18-25) after exposure to HPV-16 L1 VLP , time point 0D. Comment: List of Genes induced by VLP directly, independently of vaccination (p<0.05 and FC>1.30)

description_full:
[cell repeats an earlier one in this file: 1766 characters]


systematic_name: M41158
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in myeloid dendritic cell 3d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 3D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41159
exact_source: Supplementary Table 2a: TIV-Bcells
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in B cell 7d vs 0d in young adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41160
exact_source: Fig 6C (PO)
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832504/figure/F6/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in CD4-positive, alpha-beta memory T cell 56d vs 0d in adults (18-45) after exposure to BCG vaccine , time point 56D , administered PO (oral). Comment: top 100 most differentially expressed genes comparing Day 0 and Day 56 responses after in vitro re-stimulation with BCG-infected autologous dendritic cells

description_full:
[cell repeats an earlier one in this file: 1343 characters]


systematic_name: M41161
exact_source: Supplemental Document 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605227/bin/jem.20082292_1.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 10d vs 0d in unknown after exposure to YF-Vax/Stamaril , time point 10D

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41162
exact_source: Fig 7A
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962691/figure/F7/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes significantly correlated with anti-HBs concentration in blood in young/old adults (20-40)/(60-84) (primary vaccination) after exposure to Twinrix , time point 1D. Comment: transcripts that were differentially regulated between individuals with anti-HBs concentrations of >= 10,000 and < 10,000 IU/l

description_full:
  Many current vaccines are less immunogenic and less effective in elderly compared to younger adults due to age-related changes of the immune system. Most vaccines utilized in the elderly contain antigens, which the target population has had previous contact with due to previous vaccination or infection. Therefore, most studies investigating vaccine-induced immune responses in the elderly do not analyze responses to neo-antigens but rather booster responses. However, age-related differences in the immune response could differentially affect primary versus recall responses. We therefore investigated the impact of age on primary and recall antibody responses following hepatitis B vaccination in young and older adults. Focused gene expression profiling was performed before and 1 day after the vaccination in order to identify gene signatures predicting antibody responses. Young (20-40 years; <i>n</i> = 24) and elderly ( > 60 years; <i>n</i> = 17) healthy volunteers received either a primary series (no prior vaccination) or a single booster shot (documented primary vaccination more than 10 years ago). Antibody titers were determined at days 0, 7, and 28, as well as 6 months after the vaccination. After primary vaccination, antibody responses were lower and delayed in the elderly compared to young adults. Non-responders after the three-dose primary series were only observed in the elderly group. Maximum antibody concentrations after booster vaccination were similar in both age groups. Focused gene expression profiling identified 29 transcripts that correlated with age at baseline and clustered in a network centered around type I interferons and pro-inflammatory cytokines. In addition, smaller 8- and 6-gene signatures were identified at baseline that associated with vaccine responsiveness during primary and booster vaccination, respectively. When evaluating the kinetic changes in gene expression profiles before and after primary vaccination, a 33-gene signature, dominated by IFN-signaling, pro-inflammatory cytokines, inflammasome components, and immune cell subset markers, was uncovered that was associated with vaccine responsiveness. By contrast, no such transcripts were identified during booster vaccination. Our results document that primary differs from booster vaccination in old age, in regard to antibody responses as well as at the level of gene signatures. Clinical: www.clinicaltrialsregister.eu, this trial was registered at the EU Clinical Trial Register (EU-CTR) with the EUDRACT-Nr. 2013-002589-38.


systematic_name: M41163
exact_source: Table 3
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211276/table/T3/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell (5 to 7)d vs 0d in adults (18-40) after exposure to APSV Wetvax , time point 5 to 7D

description_full:
[cell repeats an earlier one in this file: 1030 characters]


systematic_name: M41164
exact_source: Fig 4D
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729923/figure/f4/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood responders vs poor responders in seniors (65-81) (responders (training set)) after exposure to Twinrix , time point 0D. Comment: Network inference based on the 15 markers identified as predictors of the response to the HBV vaccine.

description_full:
[cell repeats an earlier one in this file: 1114 characters]


systematic_name: M41165
exact_source: Table 3
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061512/table/T3/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell vaccinated vs candin placebo in infants (4-6m) (BCG-primed) after exposure to Modified Vaccinia Ankara (MVA) virus vaccine vector , time point 28D

description_full:
[cell repeats an earlier one in this file: 2132 characters]


systematic_name: M41166
exact_source: s4_bcl_d1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242433/bin/pone.0167488.s005.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in B cell 1d vs 0d in adults (18-49) after exposure to inactivated monovalent influenza A/Indonesia/05/2005 H5N1 split-virus vaccine , time point 1D , administered i.m.

description_full:
[cell repeats an earlier one in this file: 1986 characters]


systematic_name: M41167
exact_source: Suppl Fig 2e
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485475/bin/NIHMS65741-supplement-1.pdf
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 1d vs 0d in adults (18-64) after exposure to Pandemrix , time point 1D

description_full:
[cell repeats an earlier one in this file: 858 characters]


systematic_name: M41168
exact_source: Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068032/table/tbl1/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes positively correlated with titer response index in peripheral blood mononuclear cell in Caucasian male adults (18-40) (high responders) after exposure to Fluarix/Fluvirin , time point 1D and 3DY. Comment: Signature predictive of titer response index (TRI). Day 1 and day 3 values averaged.

description_full:
  BACKGROUND: Annual vaccination is the primary means for preventing influenza. However, great interindividual variability exists in vaccine responses, the cellular events that take place in vivo after vaccination are poorly understood, and appropriate biomarkers for vaccine responsiveness have not been developed. METHODS: We immunized a cohort of healthy male adults with a licensed trivalent influenza vaccine and performed a timed assessment of global gene expression before and after vaccination. We analyzed the relationship between gene expression patterns and the humoral immune response to vaccination. RESULTS: Marked up regulation of expression of genes involved in interferon signaling, positive IL-6 regulation, and antigen processing and presentation, were detected within 24 hours of immunization. The late vaccine response showed a transcriptional pattern suggestive of increased protein biosynthesis and cellular proliferation. Integrative analyses revealed a 494-gene expression signature--including STAT1, CD74, and E2F2--which strongly correlates with the magnitude of the antibody response. High vaccine responder status correlates with increased early expression of interferon signaling and antigen processing and presentation genes. CONCLUSIONS: The results highlight the role of a systems biology approach in understanding the molecular events that take place in vivo after influenza vaccination and in the development of better predictors of vaccine responsiveness.


systematic_name: M41169
exact_source: Table 1: Early gene expression (Day 3 - Day 0)
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520794/table/T1/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes positively correlated with memory B cell response in peripheral blood mononuclear cell in adults (50-74) after exposure to trivalent inactivated vaccine (A/California/7/09 (H1N1,), A/Perth /16/2009 (H3N2), and B/Brisbane/60/2008). , time point 3D. Comment: Association of baseline, early and late gene expression changes with peak memory B cell ELISPOT response (Day 28 - Day 0) in older individuals

description_full:
[cell repeats an earlier one in this file: 1537 characters]


systematic_name: M41170
exact_source: Suppl Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092249/bin/supp_jiu079_jiu079supp_table1.doc
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 1d vs 0d in children (0.5-14y) after exposure to FluMist , time point 1D. Comment: ~80% of cohort were white, ~50/50 Female:male

description_full:
[cell repeats an earlier one in this file: 1344 characters]


systematic_name: M41171
exact_source: Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133148/table/T1/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 28d vs 0d in adults (50-74) (in common with both HAI and VNA) after exposure to Fluarix , time point 28D , administered i.m.. Comment: Common Genesets with genes entering regression models for HAI and VNA Responses with the log2 Day 28 vs Day 0 fold-change in gene expression as the explanatory variables.

description_full:
[cell repeats an earlier one in this file: 1352 characters]


systematic_name: M41172
exact_source: Supplementary Table 2a: TIV-mDC
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in myeloid dendritic cell 7d vs 0d in young adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41173
exact_source: Supplementary Table 2a: TIV-Monocytes
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in monocyte 7d vs 0d in young adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41174
exact_source: Supplementary Table 2a: LAIV-mDC
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in myeloid dendritic cell 7d vs 0d in young adults (18-50) after exposure to FluMist , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41175
exact_source: Suppl Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092249/bin/supp_jiu079_jiu079supp_table1.doc
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 30d vs 0d in children (0.5-14y) after exposure to FluMist , time point 30D. Comment: ~80% of cohort were white, ~50/50 Female:male

description_full:
[cell repeats an earlier one in this file: 1344 characters]


systematic_name: M41176
exact_source: Suppl Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151076/bin/jiy420_suppl_supplementary_table_1.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in skin of body 3d vs 0hr in adults (70-93) (VZV challenge) after exposure to Zostavax , time point 3D

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M41177
exact_source: Fig 2C-F; Table 2
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520794/table/T2/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes positively correlated with memory B cell response at 28d in peripheral blood mononuclear cell in seniors (50-74) after exposure to Fluarix , time point 28D. Comment: selected pathways: leukocyte migration, MAP kinase activity, cytokine signaling, diabetes of the young

description_full:
[cell repeats an earlier one in this file: 1537 characters]


systematic_name: M41178
exact_source: Suppl Table 8 in additional file 9
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282650/bin/13073_2017_400_MOESM9_ESM.xls
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 7d after second dose vs 7d after first dose in adult (30-70) after exposure to Menveo/ACWYVax , time point 7D. Comment: second dose at 28 days

description_full:
  BACKGROUND: Neisseria meningitidis is a globally important cause of meningitis and septicaemia. Twelve capsular groups of meningococci are known, and quadrivalent vaccines against four of these (A, C, W and Y) are available as plain-polysaccharide and protein-polysaccharide conjugate vaccines. Here we apply contemporary methods to describe B-cell responses to meningococcal polysaccharide and conjugate vaccines. METHODS: Twenty adults were randomly assigned to receive either a meningococcal plain-polysaccharide or conjugate vaccine; one month later all received the conjugate vaccine. Blood samples were taken pre-vaccination and 7, 21 and 28 days after vaccination; B-cell responses were assessed by ELISpot, serum bactericidal assay, flow cytometry and gene expression microarray. RESULTS: Seven days after an initial dose of either vaccine, a gene expression signature characteristic of plasmablasts was detectable. The frequency of newly generated plasma cells (CXCR3<sup>+</sup>HLA-DR<sup>+</sup>) and the expression of transcripts derived from IGKC and IGHG2 correlated with immunogenicity. Notably, using an independent dataset, the expression of glucosamine (N-acetyl)-6-sulfatase was found to reproducibly correlate with the magnitude of immune response. Transcriptomic and flow cytometric data revealed depletion of switched memory B cells following plain-polysaccharide vaccine. CONCLUSIONS: These data describe distinct gene signatures associated with the production of high-avidity antibody and a plain-polysaccharide-specific signature, possibly linked to polysaccharide-induced hyporesponsiveness.


systematic_name: M41179
exact_source: Supplementary Table 2a: TIV-Monocytes
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in monocyte 7d vs 0d in young adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41180
exact_source: Fig 6C (ID)
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832504/figure/F6/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in CD4-positive, alpha-beta memory T cell 56d vs 0d in adults (18-45) after exposure to BCG vaccine , time point 56D , administered ID (intradermal). Comment: top 100 most differentially expressed genes comparing Day 0 and Day 56 responses after in vitro re-stimulation with BCG-infected autologous dendritic cells

description_full:
[cell repeats an earlier one in this file: 1343 characters]


systematic_name: M41181
exact_source: Fig 3: Non-adjuvanted
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0166354217300098?via%3Dihub#fig3
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 3d vs 0d in adults (21-51) after exposure to Influenza A (H1N1) 2009 Monovalent Vaccine (Sanofi Pasteur) , time point 3D , administered i.m.

description_full:
  The study aimed at identifying biomarkers of immune response elicited by non-adjuvanted-(NAV) and adjuvanted-(AV) H1N1(pdm09) vaccines. The results showed that despite both vaccines elicited similar levels of anti-H1N1 antibodies at day30 after vaccination, higher reactivity was observed in AV at day180. While AV induced early changes in cell-surface molecules on monocytes, CD4<sup>+</sup>, CD8<sup>+</sup> T-cells and B-cells, NAV triggered minor changes, starting later on at day3. Furthermore, AV induced a late and persistent increase in TLR gene expression after day3, except for tlr4, while NAV displayed earlier but transient tlr3/4/7/9 up-regulation. Contrasting with NAV, prominent chemokine gene expression (cxcl8,cxcl9,ccl5) and a broad spectrum up-regulation of plasmatic biomarkers (CXCL8,IL-6,IL-1beta,IL-12,IL-10) was evident in AV, which showed a major involvement of TNF and IL-10. Similarly, AV induced a robust IL-10-modulated proinflammatory storm, with early and persistent involvement of TNF-alpha/IL-12/IFN-gamma axis derived from NK-cells, CD4<sup>+</sup> and CD8<sup>+</sup> T-cells along with promiscuous production of IL-4/IL-5/IL-13. Conversely, NAV promotes a concise and restricted intracytoplasmic chemokine/cytokine response, essentially mediated by TNF-alpha and IL-4, with late IL-10 production by CD8<sup>+</sup> T-cells. Systems biology approach underscored that AV guided the formation of an imbricate network characterized by a progressive increase in the number of neighborhood connections amongst innate and adaptive immunity. In AV, the early cross-talk between innate and adaptive immunity, followed by the triad NK/CD4<sup>+</sup>/CD8<sup>+</sup> T-cells at day3, sponsored a later/robust biomarker network. These findings indicate the relevance of adjuvanted vaccination to orchestrate broad, balanced and multifactorial cellular immune events that lead ultimately to a stronger H1N1 humoral immunity.


systematic_name: M41182
exact_source: Fig 3: Adjuvanted
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0166354217300098?via%3Dihub#fig3
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 3d vs 0d in adults (21-51) after exposure to Pandemrix , time point 3D , administered i.m.

description_full:
  The study aimed at identifying biomarkers of immune response elicited by non-adjuvanted-(NAV) and adjuvanted-(AV) H1N1(pdm09) vaccines. The results showed that despite both vaccines elicited similar levels of anti-H1N1 antibodies at day30 after vaccination, higher reactivity was observed in AV at day180. While AV induced early changes in cell-surface molecules on monocytes, CD4<sup>+</sup>, CD8<sup>+</sup> T-cells and B-cells, NAV triggered minor changes, starting later on at day3. Furthermore, AV induced a late and persistent increase in TLR gene expression after day3, except for tlr4, while NAV displayed earlier but transient tlr3/4/7/9 up-regulation. Contrasting with NAV, prominent chemokine gene expression (cxcl8,cxcl9,ccl5) and a broad spectrum up-regulation of plasmatic biomarkers (CXCL8,IL-6,IL-1beta,IL-12,IL-10) was evident in AV, which showed a major involvement of TNF and IL-10. Similarly, AV induced a robust IL-10-modulated proinflammatory storm, with early and persistent involvement of TNF-alpha/IL-12/IFN-gamma axis derived from NK-cells, CD4<sup>+</sup> and CD8<sup>+</sup> T-cells along with promiscuous production of IL-4/IL-5/IL-13. Conversely, NAV promotes a concise and restricted intracytoplasmic chemokine/cytokine response, essentially mediated by TNF-alpha and IL-4, with late IL-10 production by CD8<sup>+</sup> T-cells. Systems biology approach underscored that AV guided the formation of an imbricate network characterized by a progressive increase in the number of neighborhood connections amongst innate and adaptive immunity. In AV, the early cross-talk between innate and adaptive immunity, followed by the triad NK/CD4<sup>+</sup>/CD8<sup>+</sup> T-cells at day3, sponsored a later/robust biomarker network. These findings indicate the relevance of adjuvanted vaccination to orchestrate broad, balanced and multifactorial cellular immune events that lead ultimately to a stronger H1N1 humoral immunity.


systematic_name: M41183
exact_source: Fig 3: Adjuvanted
external_details_URL: https://www.sciencedirect.com/science/article/pii/S0166354217300098?via%3Dihub#fig3
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 30d vs 0d in adults (21-51) after exposure to Pandemrix , time point 30D , administered i.m.

description_full:
  The study aimed at identifying biomarkers of immune response elicited by non-adjuvanted-(NAV) and adjuvanted-(AV) H1N1(pdm09) vaccines. The results showed that despite both vaccines elicited similar levels of anti-H1N1 antibodies at day30 after vaccination, higher reactivity was observed in AV at day180. While AV induced early changes in cell-surface molecules on monocytes, CD4<sup>+</sup>, CD8<sup>+</sup> T-cells and B-cells, NAV triggered minor changes, starting later on at day3. Furthermore, AV induced a late and persistent increase in TLR gene expression after day3, except for tlr4, while NAV displayed earlier but transient tlr3/4/7/9 up-regulation. Contrasting with NAV, prominent chemokine gene expression (cxcl8,cxcl9,ccl5) and a broad spectrum up-regulation of plasmatic biomarkers (CXCL8,IL-6,IL-1beta,IL-12,IL-10) was evident in AV, which showed a major involvement of TNF and IL-10. Similarly, AV induced a robust IL-10-modulated proinflammatory storm, with early and persistent involvement of TNF-alpha/IL-12/IFN-gamma axis derived from NK-cells, CD4<sup>+</sup> and CD8<sup>+</sup> T-cells along with promiscuous production of IL-4/IL-5/IL-13. Conversely, NAV promotes a concise and restricted intracytoplasmic chemokine/cytokine response, essentially mediated by TNF-alpha and IL-4, with late IL-10 production by CD8<sup>+</sup> T-cells. Systems biology approach underscored that AV guided the formation of an imbricate network characterized by a progressive increase in the number of neighborhood connections amongst innate and adaptive immunity. In AV, the early cross-talk between innate and adaptive immunity, followed by the triad NK/CD4<sup>+</sup>/CD8<sup>+</sup> T-cells at day3, sponsored a later/robust biomarker network. These findings indicate the relevance of adjuvanted vaccination to orchestrate broad, balanced and multifactorial cellular immune events that lead ultimately to a stronger H1N1 humoral immunity.


systematic_name: M41184
exact_source: Fig 6C (ID)
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832504/figure/F6/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in CD4-positive, alpha-beta memory T cell 56d vs 0d in adults (18-45) after exposure to BCG vaccine , time point 56D , administered ID (intradermal). Comment: top 100 most differentially expressed genes comparing Day 0 and Day 56 responses after in vitro re-stimulation with BCG-infected autologous dendritic cells

description_full:
[cell repeats an earlier one in this file: 1343 characters]


systematic_name: M41185
exact_source: Suppl Table S1
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes positively correlated with memory B cell response at 28d in peripheral blood mononuclear cell in seniors(50-74) after exposure to Fluarix , time point 0D

description_full:
[cell repeats an earlier one in this file: 1537 characters]

external_details_URL:
[cell repeats an earlier one in this file: 109 characters]


systematic_name: M41186
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in monocyte 7d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 7D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41187
exact_source: Fig 6A (PO)
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832504/figure/F6/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in CD4-positive, alpha-beta memory T cell 7d vs 0d in adults (18-45) after exposure to BCG vaccine , time point 7D , administered PO (oral). Comment: top 100 most significantly altered genes comparing Day 0 and Day 7 responses directly ex vivo

description_full:
[cell repeats an earlier one in this file: 1343 characters]


systematic_name: M41188
exact_source: Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723701/table/T1/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell stimulated vs unstimulated in adults (18-40) after exposure to Dryvax , time point 1 to 48M. Comment: top differentially expressed genes, more avail in Suppl Materials

description_full:
  Despite its eradication over 30 years ago, smallpox (as well as other orthopox viruses) remains a pathogen of interest both in terms of biodefense and for its use as a vector for vaccines and immunotherapies. Here we describe the application of mRNA-Seq transcriptome profiling to understanding immune responses in smallpox vaccine recipients. Contrary to other studies examining gene expression in virally infected cell lines, we utilized a mixed population of peripheral blood mononuclear cells in order to capture the essential intercellular interactions that occur in vivo, and would otherwise be lost, using single cell lines or isolated primary cell subsets. In this mixed cell population we were able to detect expression of all annotated vaccinia genes. On the host side, a number of genes encoding cytokines, chemokines, complement factors and intracellular signaling molecules were downregulated upon viral infection, whereas genes encoding histone proteins and the interferon response were upregulated. We also identified a small number of genes that exhibited significantly different expression profiles in subjects with robust humoral immunity compared with those with weaker humoral responses. Our results provide evidence that differential gene regulation patterns may be at work in individuals with robust humoral immunity compared with those with weaker humoral immune responses.


systematic_name: M41189
exact_source: Table 2
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475634/table/JIS546TB2/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell stimulated vs unstimulated in adults (18-40) after exposure to Dryvax , time point 9 to 34M. Comment: Original exposure within previous 4 years

description_full:
  BACKGROUND: The mechanisms underlying smallpox vaccine-induced variations in immune responses are not well understood, but are of considerable interest to a deeper understanding of poxvirus immunity and correlates of protection. METHODS: We assessed transcriptional messenger RNA expression changes in 197 recipients of primary smallpox vaccination representing the extremes of humoral and cellular immune responses. RESULTS: The 20 most significant differentially expressed genes include a tumor necrosis factor-receptor superfamily member, an interferon (IFN) gene, a chemokine gene, zinc finger protein genes, nuclear factors, and histones (P <= 1.06E(-20), q <= 2.64E(-17)). A pathway analysis identified 4 enriched pathways with cytokine production by the T-helper 17 subset of CD4+ T cells being the most significant pathway (P = 3.42E(-05)). Two pathways (antiviral actions of IFNs, P = 8.95E(-05); and IFN-alpha/beta signaling pathway, P = 2.92E(-04)), integral to innate immunity, were enriched when comparing high with low antibody responders (false discovery rate, < 0.05). Genes related to immune function and transcription (TLR8, P =.0002; DAPP1, P =.0003; LAMP3, P = 9.96E(-05); NR4A2, P <= .0002; EGR3, P = 4.52E(-05)), and other genes with a possible impact on immunity (LNPEP, P = 3.72E(-05); CAPRIN1, P =.0001; XRN1, P =.0001), were found to be expressed differentially in high versus low antibody responders. CONCLUSION: We identified novel and known immunity-related genes and pathways that may account for differences in immune response to smallpox vaccination.


systematic_name: M41190
exact_source: Suppl Table 8 in additional file 9
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282650/bin/13073_2017_400_MOESM9_ESM.xls
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 7d after second dose vs 7d after first dose in adult (30-70) after exposure to Menveo/ACWYVax , time point 7D. Comment: second dose at 28 days

description_full:
  BACKGROUND: Neisseria meningitidis is a globally important cause of meningitis and septicaemia. Twelve capsular groups of meningococci are known, and quadrivalent vaccines against four of these (A, C, W and Y) are available as plain-polysaccharide and protein-polysaccharide conjugate vaccines. Here we apply contemporary methods to describe B-cell responses to meningococcal polysaccharide and conjugate vaccines. METHODS: Twenty adults were randomly assigned to receive either a meningococcal plain-polysaccharide or conjugate vaccine; one month later all received the conjugate vaccine. Blood samples were taken pre-vaccination and 7, 21 and 28 days after vaccination; B-cell responses were assessed by ELISpot, serum bactericidal assay, flow cytometry and gene expression microarray. RESULTS: Seven days after an initial dose of either vaccine, a gene expression signature characteristic of plasmablasts was detectable. The frequency of newly generated plasma cells (CXCR3<sup>+</sup>HLA-DR<sup>+</sup>) and the expression of transcripts derived from IGKC and IGHG2 correlated with immunogenicity. Notably, using an independent dataset, the expression of glucosamine (N-acetyl)-6-sulfatase was found to reproducibly correlate with the magnitude of immune response. Transcriptomic and flow cytometric data revealed depletion of switched memory B cells following plain-polysaccharide vaccine. CONCLUSIONS: These data describe distinct gene signatures associated with the production of high-avidity antibody and a plain-polysaccharide-specific signature, possibly linked to polysaccharide-induced hyporesponsiveness.


systematic_name: M41191
exact_source: Table S3
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in CD4-positive, alpha-beta memory T cell CD4-positive T cell vs naive CD4-positive T cell in seniors (52-75) after exposure to Zostavax , time point 7 to 9D. Comment: Table S3. BV and BJ gene segment usage in VZV-reactive CD4 T cells compared to naive and memory CD4 T cells (FDR <= 0.1).

description_full:
  Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naive T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

external_details_URL:
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878824/bin/NIHMS784868-supplement-Supplemental_Text_and_Figures.pdf


systematic_name: M41192
exact_source: Table S3
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in naive T cell CD4-positive T cell vs naive CD4-positive T cell in seniors (52-75) after exposure to Zostavax , time point 7 to 9D. Comment: Table S3. BV and BJ gene segment usage in VZV-reactive CD4 T cells compared to naive and memory CD4 T cells (FDR <= 0.1).

description_full:
  Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naive T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

external_details_URL:
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878824/bin/NIHMS784868-supplement-Supplemental_Text_and_Figures.pdf


systematic_name: M41193
exact_source: Table S3
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in naive T cell CD4-positive T cell vs naive CD4-positive T cell in seniors (52-75) after exposure to Zostavax , time point 7 to 9D. Comment: Table S3. BV and BJ gene segment usage in VZV-reactive CD4 T cells compared to naive and memory CD4 T cells (FDR <= 0.1).

description_full:
  Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naive T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.

external_details_URL:
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878824/bin/NIHMS784868-supplement-Supplemental_Text_and_Figures.pdf


systematic_name: M41194
exact_source: Fig 2e
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485475/figure/F2/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell 7d vs 1d in adults (18-64) after exposure to Pandemrix , time point 7D

description_full:
[cell repeats an earlier one in this file: 858 characters]


systematic_name: M41195
exact_source: Table S1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700883/bin/pone.0067922.s004.docx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell vaccinated vs control in adults (18-55) (treated in vitro with wild-type MVA) after exposure to Modified Vaccinia Ankara (MVA) virus vaccine vector , time point 6H

description_full:
[cell repeats an earlier one in this file: 1940 characters]


systematic_name: M41196
exact_source: Fig 7
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139290/figure/F7/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes positively correlated with cell frequency CD27hi CD38hi of CD20- B cells (Plasmablasts) and CD38+ of IgD-CD27+ memory B cells in peripheral blood mononuclear cell in adults after exposure to Fluvirin/Pandemrix , time point 7D

description_full:
  A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.


systematic_name: M41197
exact_source: Suppl Table 1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4092249/bin/supp_jiu079_jiu079supp_table1.doc
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 30d vs 0d in children (0.5-14y) after exposure to Fluzone , time point 30D. Comment: ~80% of cohort were white, ~50/50 Female:male

description_full:
[cell repeats an earlier one in this file: 1344 characters]


systematic_name: M41198
exact_source: S7 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s007.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in natural killer cell 1d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 1D. Comment: Down-regulated DE RNA transcripts (down >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41199
exact_source: Supplementary Table 2a: TIV-pDC
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in plasmacytoid dendritic cell 7d vs 0d in young adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41200
exact_source: S6 Dataset
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338067/bin/pone.0118528.s006.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in myeloid dendritic cell 3d vs 0d in adults after exposure to 2011-2012 trivalent inactivated vaccine (A/California/7/09 (H1N1), A/Perth /16/2009 (H3N2), B/Brisbane/60/2008) , time point 3D. Comment: Up-regulated DE RNA transcripts (up >= 1.5x) shared between both TIV-vaccinated donors

description_full:
[cell repeats an earlier one in this file: 1424 characters]


systematic_name: M41201
exact_source: Fig 6a, Suppl Fig 8a
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell high vs low responders in adults (18-64) (medium-high adverse events score) after exposure to Pandemrix , time point 1D. Comment: Pre-vaccine transitional B cell levels and increased auto-antibodies correlate with post-vaccination AE. (a) Genes expressed differentially in low AE vs medium/high AE study subjects, both pre-vaccination and on post-vaccine days +1 and +7

description_full:
[cell repeats an earlier one in this file: 858 characters]

external_details_URL:
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485475/figure/F6/| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485475/bin/NIHMS65741-supplement-1.pdf


systematic_name: M41202
exact_source: S2 Table
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987012/bin/pone.0160970.s002.docx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in peripheral blood mononuclear cell vaccinated vs unvaccinated in adolescent/young adults (11-22) after exposure to M-M-R II , time point 7Y

description_full:
[cell repeats an earlier one in this file: 1584 characters]


systematic_name: M41203
exact_source: Supplementary Table 2a: TIV-mDC
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-3.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in myeloid dendritic cell 7d vs 0d in young adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41204
exact_source: Suppl Table 5
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140559/bin/NIHMS301940-supplement-6.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes positively correlated with HAI response at 28d in peripheral blood mononuclear cell in adults (18-50) after exposure to Fluarix/Fluvirin , time point 7D. Comment: Supplementary Table 5: All genes whose expression (d3/d0 or d7/d0) correlates to the fold increase in HAI titers (d28/d0).

description_full:
[cell repeats an earlier one in this file: 949 characters]


systematic_name: M41205
exact_source: Table 3
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in peripheral blood mononuclear cell 7d or 14d vs 0d in adults (15-25) after exposure to Attenuvax , time point 7 or 14D , administered subcutaneous

description_full:
  Cellular immunity to measles vaccination is not fully understood at the effector response and gene expression levels. We enrolled 15 healthy individuals (15-25 years old) previously vaccinated with two doses of measles-mumps-rubella-II vaccine to characterize their cellular immunity. We detected a spectrum of lymphoproliferative response (median stimulation indices of 3.4), low precursor frequencies of interferon-gamma (median 0.11%) and interleukin-4 (median 0.05%) by Elispot, and cosecretion of Th1 and Th2 cytokines after measles virus stimulation. Further, global gene expression was examined in five subjects from this cohort after vaccination with an additional dose of measles vaccine (Attenuax, Merck) to identify the genes involved in measles immunity. Linear mixed effect models were used to identify genes significantly up or downregulated in vivo between baseline and Days 7 and 14 after measles vaccination. Measles vaccination induced upregulation of a set of 80 genes, which play a role in measles immunity, signal transduction, apoptosis, cell proliferation, and metabolic pathways. Among the 34 genes that were downregulated, only interferon-alpha is known to have a direct role in measles immunity. This study suggests that measles vaccination leads to activation of multiple cellular mechanisms that can override the immunosuppressant effects of the measles virus and induce immunity.


systematic_name: M41206
exact_source: Fig2c
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485475/figure/F2/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in T cell 7d vs 1d in adults (18-64) after exposure to Pandemrix (A/California/7/09 (H1N1)) , time point 7D. Comment: - roughly 60/40 female:male ratio, over 70% were Causasian

description_full:
[cell repeats an earlier one in this file: 858 characters]


systematic_name: M41207
exact_source: Fig2c
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485475/figure/F2/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in T cell 1d vs 0d in adults (18-64) after exposure to Pandemrix (A/California/7/09 (H1N1)) , time point 1D. Comment: - roughly 60/40 female:male ratio, over 70% were Causasian

description_full:
[cell repeats an earlier one in this file: 858 characters]


systematic_name: M41208
exact_source: Table 1: Early gene expression (Day 3 - Day 0)
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520794/table/T1/
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes negatively correlated with memory B cell response in peripheral blood mononuclear cell in adults (50-74) after exposure to trivalent inactivated vaccine (A/California/7/09 (H1N1,), A/Perth /16/2009 (H3N2), and B/Brisbane/60/2008). , time point 3D. Comment: Association of baseline, early and late gene expression changes with peak memory B cell ELISPOT response (Day 28 - Day 0) in older individuals

description_full:
[cell repeats an earlier one in this file: 1537 characters]


systematic_name: M41209
exact_source: Suppl Table 2
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834766/bin/Table_2.XLSX
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes up-regulated in blood 7d vs 0hr in adults (18-45) after exposure to CN54gp140 adjuvanted with GLA-AF , time point 7D , administered i.m.

description_full:
[cell repeats an earlier one in this file: 2100 characters]


systematic_name: M41210
exact_source: s4_dnc_d1
external_details_URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242433/bin/pone.0167488.s005.xlsx
source_species_code: HS
contributor: HIPC SIGNATURES
contrib_organization: NIAID/HIPC SIGNATURES
description_brief:
  Genes down-regulated in dendritic cell 1d vs 0d in adults (18-49) after exposure to inactivated monovalent influenza A/Indonesia/05/2005 H5N1 split-virus vaccine , time point 1D , administered i.m.

description_full:
[cell repeats an earlier one in this file: 1986 characters]


systematic_name: M39048
exact_source: Table S2. Binarized Genes Across Cell Types, Related to Figure 1: Human Embryo
source_species_code: HS
GEO_id: GSE76381
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Cell types are named using anatomical and functional mnemonics prefixed by 'm' or'h' to indicate mouse and human respectively: OMTN, oculomotor and trochlear nucleus; Sert, serotonergic; NbM, medial neuroblast; NbDA, neuroblast dopaminergic; DA0-2, dopaminergic neurons; RN, red nucleus; Gaba1-2, GABAergic neurons; mNbL1-2, lateral neuroblasts; NbML1-5, mediolateral neuroblasts; NProg, neuronal progenitor; Prog, progenitor medial floorplate (FPM), lateral floorplate (FPL), midline (M), basal plate (BP); Rgl1-3, radial glia-like cells; Mgl, microglia; Endo, endothelial cells; Peric, pericytes; Epend, ependymal; OPC, oligodendrocyte precursor cells.


systematic_name: M39105
external_details_URL: http://human-liver-cell-atlas.ie-freiburg.mpg.de/
source_species_code: HS
GEO_id: GSE124395
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table 1 Gene expression signatures of all clusters. Official gene symbol, mean expression across all genes not contained within a cluster (mean.ncl), mean expression across all genes contained within a cluster (mean.cl), fold change between cluster and non-cluster cells (fc), differential expression p-value (pv, see Methods), and Benjamini-Hochberg corrected p-value are given. Only genes with P<0.01 are shown for each cluster. (n= 10,372 cells). These cluster markers were further filtered to include only genes with a FC>2.


systematic_name: M39168
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Alpha


systematic_name: M39169
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Beta


systematic_name: M39170
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Delta


systematic_name: M39171
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). PP


systematic_name: M39172
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Epsilon


systematic_name: M39173
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Duct


systematic_name: M39174
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Acinar


systematic_name: M39175
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Mesenchyme


systematic_name: M39176
source_species_code: HS
GEO_id: GSE85241
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Differential Gene Expression, Related to Figure 1: Differentially expressed genes between each cell type compared to all others (across all donors). Endothelial


systematic_name: M39177
external_details_URL: http://www.altanalyze.org/ICGS/HCA/Viewer.php
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table E5: Gene-Associations. Global view of cells from all donors. Combined resolved progenitor and committed cell population predictions for SPRING analysis of the associated marker genes. 1-s2.0-S0301472X18308051-mmc8. Genes with Pearson rho > 0.1, Pearson p-value <0.05.


systematic_name: M39210
source_species_code: HS
GEO_id: GSE97104
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table EV1A: Top 100 transcriptional markers identified for each cluster after latent variable regression for cell cycle and technical covariates


systematic_name: M39220
source_species_code: HS
GEO_id: GSE121862
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Data 7: Differentially expressed genes between all clusters. Supplementary Data 5: Cluster Annotations.


systematic_name: M39250
source_species_code: HS
GEO_id: GSE109205
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1: The table provides list of significantly expressed genes for each of the 11 clusters compared to all other clusters


systematic_name: M39272
source_species_code: HS
GEO_id: GSE139522
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table 3. Enriched gene expression lists for human OE cell clusters identified by scRNA-seq. Genes with Log2(FC)>1, padj<0.05.


systematic_name: M39307
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 6, Filtered CompactA genes


systematic_name: M39308
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 6, Filtered TrabecularA genes


systematic_name: M39309
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 7, Filtered CompactV genes


systematic_name: M39310
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 7, Filtered TrabecularV genes


systematic_name: M39311
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 9, Filtered C1 CM-A, 5 week genes.


systematic_name: M39312
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 9, Filtered C2 CM-V, 5 week genes.


systematic_name: M39313
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 11, Filtered C1 (LV) genes.


systematic_name: M39314
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 11, Filtered C2 (RV) genes.


systematic_name: M39315
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 11, Filtered C3 (LA) genes.


systematic_name: M39316
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S3. Second-Level Clustering Results and Gene Groups of Dynamic Changing of CMs, Related to Figures 2, 3, and S3. Sheet 11, Filtered C4 (RA) genes.


systematic_name: M39317
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S4. Second-Level Clustering Results of Fibroblast-like Cells and Gene Groups of Dynamic Changing of Cardiac Fibroblasts, Related to Figures 4 and S4, Sheet2 Cluster C1


systematic_name: M39318
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S4. Second-Level Clustering Results of Fibroblast-like Cells and Gene Groups of Dynamic Changing of Cardiac Fibroblasts, Related to Figures 4 and S4, Sheet2 Cluster C2


systematic_name: M39319
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S5. Clustering Results of Valvar Cells and Cardiac Endothelial Cells, Related to Figure 5. Sheet3 Filtered C1 (Endocardial cell).


systematic_name: M39320
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S5. Clustering Results of Valvar Cells and Cardiac Endothelial Cells, Related to Figure 5. Sheet3 Filtered C2 (Coronary vascular endothelial cell).


systematic_name: M39321
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S5. Clustering Results of Valvar Cells and Cardiac Endothelial Cells, Related to Figure 5. Sheet3 Filtered C3 (Vascular endothelial cell).


systematic_name: M39322
source_species_code: HS
GEO_id: GSE106118
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S5. Clustering Results of Valvar Cells and Cardiac Endothelial Cells, Related to Figure 5. Sheet3 Filtered C4 (Valvar endothelial cell).


systematic_name: M41702
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Most stromal cells from selectable follicle C clustered in CL1 (Fig. 3a). Although stromal clusters (CL0, CL1) showed high expression of GNL3 and ARID5B (Fig. 8d), CL0 expressed high levels of XBP1 and SELK (Fig. 8e), both involved in endoplasmic reticulum (ER)-stress-induced apoptosis, whereas CL1 expressed high levels of GPRC5A and TNFRS12A (Fig. 8f).

exact_source:
  Supplementary Data 2 (complete underlying data received from authors), avg_logFC > 0.25, p_val_adj <0.05


systematic_name: M41704
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  TC from (early atretic) follicle D and present in stromal samples were mainly present in CL2 and CL6 (Fig. 4a, Supplementary Fig. 2c), suggesting that those may represent atretic TC. The TC in CL2 and CL6 expressed IFITM3, lower levels of COL3A1 and higher levels of FOS and IGFBP5 compared to the TC in CL5 (Fig. 8a).

exact_source:
  Supplementary Data 2 (complete underlying data received from authors), avg_logFC > 0.25, p_val_adj <0.05


systematic_name: M41705
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Pseudotime analysis using Monocle 3 alpha, that places the progenitor cell population in the middle of a longer trajectory segment, revealed that pGC (CL15) branched to mural GC (CL11) and mature cumulus GC (CL8 and CL3) (Fig. 6a).

exact_source:
[cell repeats an earlier one in this file: 104 characters]


systematic_name: M41706
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  The ovaries analyzed showed a pronounced population of CD53high/CXCR4high immune cells (Fig. 2e), including separate clusters for adaptive T lymphocytes and Natural Killer (NK) cells (CL4 and CL12), B lymphocytes (CL18), and innate immune system, such as monocytes and macrophages (CL13)

exact_source:
[cell repeats an earlier one in this file: 104 characters]


systematic_name: M41707
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  TC from (healthy) follicles, such as follicles A, B, and C, were mainly clustered in CL5 (Fig. 4a), characterized by expression of known markers PTH1, APOD, APOC1, and several genes not earlier associated with TC, such as WFDC1, MATN2, COLEC11 (Fig. 7a). TC from the small antral follicles A and B did not overlap with TC from selectable follicle C in CL5 (Fig. 4a).

exact_source:
[cell repeats an earlier one in this file: 104 characters]


systematic_name: M41709
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  We identified three separate clusters (CL) of endothelial cells (CL7, CL9, CL16) expressing markers associated with lymph and blood vascular system (such as PECAM1, CD34, CTGF), but also associated with remodeling and inflammatory response (such as TXNIP, ANGPT2) (Fig. 3a-d). The DEGs of CL7 (such as CCL14, SOCS3, EGFL7) and CL16 (such as CCL21, TFF3) are linked to angiogenesis and lymphatics, respectively, while DEGs of CL9 (TM4SF1, NMMT) were more related to regulation of apoptosis (Fig. 3c, d).

exact_source:
[cell repeats an earlier one in this file: 104 characters]


systematic_name: M41712
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  The GC of CL10 were negative for several GC markers, such as VCAN and FST (Fig. 4b), but were also negative for KRT18 (Fig. 4b), similarly to pan-KRT-negative GC in atretic follicles (Fig. 4d). This suggested that CL10 could represent GC in the early stages of atresia.

exact_source:
[cell repeats an earlier one in this file: 104 characters]


systematic_name: M41716
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  The clusters of smooth muscle cells (CL14, CL17) also showed features of growth and remodeling: many DEGs of CL17 (such as CRYAB, GJA4) were involved in regulation of immune response and apoptosis, whereas DEGs of CL14 (such as ACTA2, PLN, ADIRF, and MYH11) associated with mature smooth muscle cells (Fig. 3e-g).

exact_source:
[cell repeats an earlier one in this file: 104 characters]


systematic_name: M41717
external_details_URL: https://doi.org/10.1038/s41467-019-11036-9
source_species_code: HS
GEO_id: GSE118127
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  The GC of small antral follicles (1-2_mm diameter) clustered pronouncedly in cluster (CL15) showing WT1high/EGR4high/VCANlow/FSTlow expression (Fig. 4b), suggesting that at that stage mural and cumulus GC still have a common progenitor (pGC) signature.

exact_source:
[cell repeats an earlier one in this file: 104 characters]


systematic_name: M41743
source_species_code: HS
GEO_id: GSE130646
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table S1 (41598_2019_57110_MOESM2_ESM), genes annotated as cell type: Endothelial Cells.


systematic_name: M41746
source_species_code: HS
GEO_id: GSE130646
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table S1 (41598_2019_57110_MOESM2_ESM), genes annotated as cell type: Smooth Muscle Cells.


systematic_name: M41747
source_species_code: HS
GEO_id: GSE130646
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table S1 (41598_2019_57110_MOESM2_ESM), genes annotated as cell type: PCV Endothelial Cells.


systematic_name: M41748
source_species_code: HS
GEO_id: GSE130646
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table S1 (41598_2019_57110_MOESM2_ESM), genes annotated as cell type: Satellite Cells.


systematic_name: M41750
source_species_code: HS
GEO_id: GSE130646
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Supplementary Table S1 (41598_2019_57110_MOESM2_ESM), genes annotated as cell type: FBN1+ FAP Cells.


systematic_name: M43600
external_details_URL: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8478974/
source_species_code: HS
GEO_id: GSE147979,GSE137537
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Occular cell types curated from Gautam and Hamashima et al. Multi-species single-cell transcriptomic analysis of ocular compartment regulons

exact_source:
  Supplementary Data 2: One-sided Wilcoxon rank-sum test p-values for the markers of cell types in iris/ciliary body. pAdj<0.05,Log2FC>1.5.


systematic_name: M43601
external_details_URL: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8478974/
source_species_code: HS
GEO_id: GSE147979,GSE137537
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Occular cell types curated from Gautam and Hamashima et al. Multi-species single-cell transcriptomic analysis of ocular compartment regulons

exact_source:
  Supplementary Data 2: One-sided Wilcoxon rank-sum test p-values for the markers of cell types in cornea. pAdj<0.05,Log2FC>1.5.


systematic_name: M43604
external_details_URL: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8478974/
source_species_code: HS
GEO_id: GSE147979,GSE137537
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
[cell repeats an earlier one in this file: 140 characters]

exact_source:
  Supplementary Data 2: One-sided Wilcoxon rank-sum test p-values for the markers of cell types in choroid/sclera. pAdj<0.05,Log2FC>1.5.


systematic_name: M45029
exact_source: Supplemental tables 11
source_species_code: HS
GEO_id: GSE150724
contributor: Leon van Gurp
contrib_organization: Universit&eacute; de Gen&egrave;ve
description_brief:
  Transcriptomic signature geneset for human pancreatic alpha cells derived from meta-analyzing multiple single cell RNAseq datasets

description_full:
  Single cell RNAseq data from human pancreatic islets was downloaded from 7 previously published datasets. Pairwise differential expression was calculated between all islet cell types in each dataset, and results were integrated to compose a core list of ID genes for each cell types, organised primarily on the number of analyses a gene was detected in. A machine-learning based approach was used to threshold which genes were included in the final ID geneses, and these genesets were then cross validated in three independent datasets to demonstrate they outperformed previously published lists of ID genes.


systematic_name: M45030
exact_source: Supplemental tables 11
source_species_code: HS
GEO_id: GSE150724
contributor: Leon van Gurp
contrib_organization: Universit&eacute; de Gen&egrave;ve
description_brief:
  Transcriptomic signature geneset for human pancreatic beta cells derived from meta-analyzing multiple single cell RNAseq datasets

description_full:
  Single cell RNAseq data from human pancreatic islets was downloaded from 7 previously published datasets. Pairwise differential expression was calculated between all islet cell types in each dataset, and results were integrated to compose a core list of ID genes for each cell types, organised primarily on the number of analyses a gene was detected in. A machine-learning based approach was used to threshold which genes were included in the final ID geneses, and these genesets were then cross validated in three independent datasets to demonstrate they outperformed previously published lists of ID genes.


systematic_name: M45031
exact_source: Supplemental tables 11
source_species_code: HS
GEO_id: GSE150724
contributor: Leon van Gurp
contrib_organization: Universit&eacute; de Gen&egrave;ve
description_brief:
  Transcriptomic signature geneset for human pancreatic gamma cells derived from meta-analyzing multiple single cell RNAseq datasets

description_full:
  Single cell RNAseq data from human pancreatic islets was downloaded from 7 previously published datasets. Pairwise differential expression was calculated between all islet cell types in each dataset, and results were integrated to compose a core list of ID genes for each cell types, organised primarily on the number of analyses a gene was detected in. A machine-learning based approach was used to threshold which genes were included in the final ID geneses, and these genesets were then cross validated in three independent datasets to demonstrate they outperformed previously published lists of ID genes.


systematic_name: M45032
exact_source: Supplemental tables 11
source_species_code: HS
GEO_id: GSE150724
contributor: Leon van Gurp
contrib_organization: Universit&eacute; de Gen&egrave;ve
description_brief:
  Transcriptomic signature geneset for human pancreatic delta cells derived from meta-analyzing multiple single cell RNAseq datasets

description_full:
[cell repeats an earlier one in this file: 608 characters]


description_brief: ASPN+ chondrocyte
systematic_name: M45663
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: ASPN+ chondrocyte


description_brief: Adventitial fibro
systematic_name: M45664
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Adventitial fibro


description_brief: Airway fibro
systematic_name: M45665
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Airway fibro


description_brief: Alveolar fibro
systematic_name: M45666
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Alveolar fibro


description_brief: Early fibro
systematic_name: M45667
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Early fibro


description_brief: Early mesothelial
systematic_name: M45668
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Early mesothelial


description_brief: Interm chondrocyte
systematic_name: M45669
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Interm chondrocyte


description_brief: Interm fibro
systematic_name: M45670
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Interm fibro


description_brief: Late airway SMC
systematic_name: M45671
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Late airway SMC


description_brief: Late mesothelial
systematic_name: M45672
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Late mesothelial


description_brief: Mesenchymal 1
systematic_name: M45674
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Mesenchymal 1


description_brief: Mesenchymal 2
systematic_name: M45675
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Mesenchymal 2


description_brief: Mesenchymal 3
systematic_name: M45676
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Mesenchymal 3


description_brief: Mid airway SMC 1
systematic_name: M45677
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Mid airway SMC 1


description_brief: Mid airway SMC 2
systematic_name: M45678
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Mid airway SMC 2


description_brief: Mid mesothelial
systematic_name: M45680
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Mid mesothelial


description_brief: Myofibro 1
systematic_name: M45681
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Myofibro 1


description_brief: Myofibro 2
systematic_name: M45682
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Myofibro 2


description_brief: Myofibro 3
systematic_name: M45683
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Myofibro 3


description_brief: Resting chondrocyte
systematic_name: M45685
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Resting chondrocyte


description_brief: Vascular SMC 1
systematic_name: M45686
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Vascular SMC 1


description_brief: Vascular SMC 2
systematic_name: M45687
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C0 Annotated Cell: Vascular SMC 2


description_brief: Early airway progenitor
systematic_name: M45691
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Early airway progenitor


description_brief: Early stalk
systematic_name: M45692
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Early stalk


description_brief: GHRL+ NE precursor
systematic_name: M45694
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: GHRL+ NE precursor


description_brief: GHRL+ neuroendocrine
systematic_name: M45695
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: GHRL+ neuroendocrine


description_brief: Interm neuroendocrine
systematic_name: M45696
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Interm neuroendocrine


description_brief: Late airway progenitor
systematic_name: M45697
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Late airway progenitor


description_brief: Late basal
systematic_name: M45698
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Late basal


description_brief: Late stalk
systematic_name: M45699
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Late stalk


description_brief: MUC5AC+ ASCL1+ progenitor
systematic_name: M45701
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: MUC5AC+ ASCL1+ progenitor


description_brief: Mid airway progenitor
systematic_name: M45702
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Mid airway progenitor


description_brief: Proximal basal
systematic_name: M45706
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Proximal basal


description_brief: Proximal secretory 1
systematic_name: M45707
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Proximal secretory 1


description_brief: Proximal secretory 2
systematic_name: M45708
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Proximal secretory 2


description_brief: Proximal secretory 3
systematic_name: M45709
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Proximal secretory 3


description_brief: Proximal secretory progenitors
systematic_name: M45710
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Proximal secretory progenitors


description_brief: Pulmonary NE precursor
systematic_name: M45711
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Pulmonary NE precursor


description_brief: Pulmonary neuroendocrine
systematic_name: M45712
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C1 Annotated Cell: Pulmonary neuroendocrine


description_brief: APOE+ M&phi;1
systematic_name: M45716
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: APOE+ M&phi;1


description_brief: APOE+ M&phi;2
systematic_name: M45717
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: APOE+ M&phi;2


description_brief: CXCL9+ M&phi;
systematic_name: M45721
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: CXCL9+ M&phi;


description_brief: Cycling DC
systematic_name: M45722
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: Cycling DC


description_brief: Megakaryocyte
systematic_name: M45731
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: Megakaryocyte


description_brief: Myelocyte-like
systematic_name: M45732
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: Myelocyte-like


description_brief: Neutrophil
systematic_name: M45733
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: Neutrophil


description_brief: Non-cla. mono.
systematic_name: M45734
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: Non-cla. mono.


description_brief: Promonocyte-like
systematic_name: M45736
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: Promonocyte-like


description_brief: Promyelocyte-like
systematic_name: M45737
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: Promyelocyte-like


description_brief: S100A12-hi cla. mono.
systematic_name: M45738
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: S100A12-hi cla. mono.


description_brief: SPP1+ M&phi;
systematic_name: M45740
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: SPP1+ M&phi;


description_brief: pre-pDC/DC5
systematic_name: M45744
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C2 Annotated Cell: pre-pDC/DC5


description_brief: Arterial endo
systematic_name: M45746
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Arterial endo


description_brief: Cycling definitive erythroblast
systematic_name: M45747
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Cycling definitive erythroblast


description_brief: Definitive erythroblast
systematic_name: M45748
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Definitive erythroblast


description_brief: Definitive erythrocyte
systematic_name: M45749
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Definitive erythrocyte


description_brief: Definitive reticulocyte
systematic_name: M45750
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Definitive reticulocyte


description_brief: GRIA2+ arterial endo
systematic_name: M45752
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: GRIA2+ arterial endo


description_brief: HMOX1+ primitive erythroblast
systematic_name: M45753
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: HMOX1+ primitive erythroblast


description_brief: Intermediate lymphatic endo
systematic_name: M45754
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Intermediate lymphatic endo


description_brief: Lymphatic endo
systematic_name: M45756
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Lymphatic endo


description_brief: Primitive erythrocyte
systematic_name: M45759
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Primitive erythrocyte


description_brief: SCG3+ lymphatic endothelial
systematic_name: M45760
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: SCG3+ lymphatic endothelial


description_brief: Venous endo
systematic_name: M45761
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C3 Annotated Cell: Venous endo


description_brief: Activated NK
systematic_name: M45762
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C4 Annotated Cell: Activated NK


description_brief: CD56bright NK
systematic_name: M45765
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C4 Annotated Cell: CD56bright NK


description_brief: Cycling NK
systematic_name: M45767
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C4 Annotated Cell: Cycling NK


description_brief: T&alpha;&beta;_Entry
systematic_name: M45777
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C4 Annotated Cell: T&alpha;&beta;_Entry


description_brief: CD5+ CCL22+ mature B
systematic_name: M45778
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C5 Annotated Cell: CD5+ CCL22+ mature B


description_brief: CD5+ CCL22- mature B
systematic_name: M45779
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C5 Annotated Cell: CD5+ CCL22- mature B


description_brief: CD5- Mature B
systematic_name: M45780
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C5 Annotated Cell: CD5- Mature B


description_brief: Large pre-B
systematic_name: M45782
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C5 Annotated Cell: Large pre-B


description_brief: Late pro-B
systematic_name: M45784
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C5 Annotated Cell: Late pro-B


description_brief: &lambda; small pre-B
systematic_name: M45788
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C5 Annotated Cell: &lambda; small pre-B


description_brief: Deuterosomal
systematic_name: M45789
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C6 Annotated Cell: Deuterosomal


description_brief: MUC16+ ciliated
systematic_name: M45790
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C6 Annotated Cell: MUC16+ ciliated


description_brief: COL20A1+ Schwann
systematic_name: M45791
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: COL20A1+ Schwann


description_brief: FGFBP2+ Neural progenitor
systematic_name: M45792
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: FGFBP2+ Neural progenitor


description_brief: KCNIP4+ neuron
systematic_name: M45793
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: KCNIP4+ neuron


description_brief: Late Schwann
systematic_name: M45794
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: Late Schwann


description_brief: MFNG+ DBH+ neuron
systematic_name: M45795
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: MFNG+ DBH+ neuron


description_brief: Mid Schwann
systematic_name: M45796
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: Mid Schwann


description_brief: PCP4+ neuron
systematic_name: M45797
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: PCP4+ neuron


description_brief: Proliferating Schwann
systematic_name: M45798
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: Proliferating Schwann


description_brief: SST+ neuron
systematic_name: M45799
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: SST+ neuron


description_brief: Schwann precursor
systematic_name: M45800
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: Schwann precursor


description_brief: TM4SF4+ CHODL+ neuron
systematic_name: M45801
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: TM4SF4+ CHODL+ neuron


description_brief: TM4SF4+ PENK+ neuron
systematic_name: M45802
external_details_URL: https://lungcellatlas.org
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
exact_source:
  Table S1. Cell-type markers, related to Figures 2, 4, 7, and S1. Sheet C7 Annotated Cell: TM4SF4+ PENK+ neuron


systematic_name: M48347
exact_source: adm7506_Data_S5: Granulosa - 96 Genes
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
  The reproductive and endocrine functions of the ovary involve spatially defined interactions among specialized cell populations. Despite the ovary's importance in fertility and endocrine health, functional attributes of ovarian cells are largely uncharacterized. Here, we profiled >18,000 genes in 257 regions from the ovaries of two premenopausal donors to examine the functional units in the ovary. We also generated single-cell RNA sequencing data for 21,198 cells from three additional donors and identified four major cell types and four immune cell subtypes. Custom selection of sampling areas revealed distinct gene activities for oocytes, theca, and granulosa cells. These data contributed panels of oocyte-, theca-, and granulosa-specific genes, thus expanding the knowledge of molecular programs driving follicle development. Serial samples around oocytes and across the cortex and medulla uncovered previously unappreciated variation of hormone and extracellular matrix remodeling activities. This combined spatial and single-cell atlas serves as a resource for future studies of rare cells and pathological states in the ovary.


systematic_name: M48350
exact_source: adm7506_Data_S8: Endothelial > 0
source_species_code: HS
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Marker genes selected by filtering the centroid data for genes with a value > 0 for the given cell type

description_full:
[cell repeats an earlier one in this file: 1139 characters]


systematic_name: M8599
exact_source: Table 1S: kras-DN Up regulated genes
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in NIH3T3 cells (fibroblasts) transformed by activated KRAS [GeneID=3845] vs those reverted to normal cells upon over-expression of a dominant negative form of CDC25 [GeneID=5923].

description_full:
  Mutational activation of ras genes is required for the onset and maintenance of different malignancies. Here we show, using a combination of molecular physiology, nutritional perturbations and transcriptional profiling, that full penetrance of phenotypes related to oncogenic Ras activation, including the shift of carbon metabolism towards fermentation and upregulation of key cell cycle regulators, is dependent upon glucose availability. These responses are induced by Ras activation, being specifically reverted by downregulation of the Ras pathway obtained through the expression of a dominant-negative Ras-specific guanine nucleotide exchange protein. Our data allow to link directly to ras activation the alteration in energy metabolism of cancer cells, their fragility towards glucose shortage and ensuing apoptotic death.


systematic_name: M5312
exact_source: Table 1S: kras-DN Down regulated genes
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in NIH3T3 cells (fibroblasts) transformed by activated KRAS [GeneID=3845] vs those reverted to normal cells upon over-expression of a dominant negative form of CDC25 [GeneID=5923].

description_full:
[cell repeats an earlier one in this file: 830 characters]


systematic_name: M8795
exact_source: Table 1S: kras-wt Up regulated genes
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in transformed NIH3T3 cells (fibroblasts transformed by activated KRAS [GeneID=3845]) vs normal cells.

description_full:
[cell repeats an earlier one in this file: 830 characters]


systematic_name: M12828
exact_source: Table 1S: DN-wt Up regulated genes
source_species_code: MM
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in reverted NIH3T3 cells (fibroblasts transformed by activated KRAS [GeneID=3845] which then reverted to normal cells upon stable over-expression of a dominant negative form of CDC25 [GeneID=5923]) vs normal fibroblasts.

description_full:
[cell repeats an earlier one in this file: 830 characters]


systematic_name: M17040
exact_source: table 1: delta(i) < 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblast) isolated from HRAS [GeneID=3265] knockout mice.

description_full:
  We characterized differential gene expression profiles of fibroblast cell lines harboring single or double-homozygous null mutations in H-ras and N-ras. Whereas the expression level of the individual H-, N- and K-ras genes appeared unaffected by the presence or absence of the other ras loci, significant differences were observed between the expression profiles of cells missing N-ras and/or H-ras. Absence of N-ras produced much stronger effects than absence of H-ras over the profile of the cellular transcriptome. N-ras(-/-) and H-ras(-/-) fibroblasts displayed rather antagonistic expression profiles and the transcriptome of H-ras(-/-) cells was significantly closer to that of wild-type fibroblasts than to that of N-ras(-/-) cells. Classifying all differentially expressed genes into functional categories suggested specific roles for H-Ras and N-Ras. It was particularly striking in N-ras(-/-) cells the upregulation of a remarkable number of immunity-related genes, as well as of several loci involved in apoptosis. Reverse-phase protein array assays demonstrated in the same N-ras(-/-) cells the overexpression and nuclear migration of tyrosine phosphorylated signal transducer and activator of transcription 1 (Stat1) which was concomitant with transcriptional activation mediated by interferon-stimulated response elements. Significantly enhanced numbers of apoptotic cells were also detected in cultures of N-ras(-/-) cells. Our data support the notion that different Ras isoforms play functionally distinct cellular roles and indicate that N-Ras is significantly involved in immune modulation/host defense and apoptotic responses.


systematic_name: M5355
exact_source: Table 3: delta(i) < 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblasts) isolated from HRAS and NRAS [GeneID=3265;4893] double knockout mice.

description_full:
[cell repeats an earlier one in this file: 1645 characters]


systematic_name: M12848
exact_source: Table 2: delta(i) < 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MEF cells (embryonic fibroblast) isolated from NRAS [GeneID=4893] knockout mice.

description_full:
[cell repeats an earlier one in this file: 1645 characters]


systematic_name: M4263
exact_source: Table 1S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in follicular epithelial stem cells after transgenic expression of GR [GeneID=2908] under control of the keratin5 (K5) [GeneID=3852] promoter.

description_full:
  Glucocorticoids are potent inhibitors of mouse skin tumorigenesis. The glucocorticoid control of cellular functions is mediated via the glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated transgenic mice overexpressing GR under control of the keratin5 (K5) promoter, and showed that K5.GR animals are resistant to skin carcinogenesis. Follicular epithelial stem cells (SCs), located in the bulge region of the hair follicle, are believed to be one of the target cells for skin carcinogenesis. We found that the number of putative hair follicle SC detected as label-retaining cells was significantly less in the K5.GR transgenics compared to wild type (w.t.) littermates. We also showed that GR overexpression led to a reduction in the clonogenicity of the follicular epithelial SCs. We evaluated the global effect of GR on gene expression in a population of follicular SC-enriched bulge keratinocytes isolated by fluorescence activated cell sorting. We found that GR affected the expression of numerous bulge SC 'signature' genes, genes involved in the maintenance of SC and progenitor cells of non-epidermal origin and proapoptotic genes. Our findings underscore the important role of GR signaling in the homeostasis of follicular epithelial SCs, and suggest that the reduction in their number may underlie the tumor suppressor effect of GR in the skin.


systematic_name: M7876
exact_source: Table 2S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in follicular epithelial stem cells after transgenic expression of GR [GeneID=2908] under control of the keratin5 (K5) [GeneID=3852] promoter.

description_full:
  Glucocorticoids are potent inhibitors of mouse skin tumorigenesis. The glucocorticoid control of cellular functions is mediated via the glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated transgenic mice overexpressing GR under control of the keratin5 (K5) promoter, and showed that K5.GR animals are resistant to skin carcinogenesis. Follicular epithelial stem cells (SCs), located in the bulge region of the hair follicle, are believed to be one of the target cells for skin carcinogenesis. We found that the number of putative hair follicle SC detected as label-retaining cells was significantly less in the K5.GR transgenics compared to wild type (w.t.) littermates. We also showed that GR overexpression led to a reduction in the clonogenicity of the follicular epithelial SCs. We evaluated the global effect of GR on gene expression in a population of follicular SC-enriched bulge keratinocytes isolated by fluorescence activated cell sorting. We found that GR affected the expression of numerous bulge SC 'signature' genes, genes involved in the maintenance of SC and progenitor cells of non-epidermal origin and proapoptotic genes. Our findings underscore the important role of GR signaling in the homeostasis of follicular epithelial SCs, and suggest that the reduction in their number may underlie the tumor suppressor effect of GR in the skin.


systematic_name: M5392
exact_source: Table 5S: RhoAi > 1
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in NIH3T3 cells (fibroblasts) after treatment with Y27632 [PubChem=123862], an inhibitor of ROCK proteins; the changes did not depend on expression of constitutively active (Q63L) form of RHOA [GeneID=387].

description_full:
[cell repeats an earlier one in this file: 1498 characters]


systematic_name: M3034
exact_source: Table 3S: RhoAi < 1 & RhoA > 1
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in NIH3T3 cells (fibroblasts) transformed by  expression of contitutively active (Q63L) form of RHOA [GeneID=387] off plasmid vector; their expression reverted completely after treatment with Y27632 [PubChem=123862], an inhibitor of ROCK proteins.

description_full:
[cell repeats an earlier one in this file: 1498 characters]


systematic_name: M6384
exact_source: Table 1: Increased in tumors
source_species_code: MM
GEO_id: GSE2528
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the 65 most significantly changed (p<0.01) genes identified by two analytical methods in the mammary tumors induced by transgenic expression of ERBB2 [GeneID=2064].

description_full:
[cell repeats an earlier one in this file: 1973 characters]


systematic_name: M15209
exact_source: Table 2: Increased in adjacent erbB2/neu samples
source_species_code: MM
GEO_id: GSE2528
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from top 82 genes out of the 324-gene signature identified in the pre-neoplastic tissue adjacent to the mammary tumors induced by transgenic expression of ERBB2 [GeneID=2064].

description_full:
[cell repeats an earlier one in this file: 1973 characters]


systematic_name: M1110
exact_source: Table AS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the set A (Fig. 5a): specific to cells expressing MLL-AF4 [GeneID=4297;4299] fusion protein alone.

description_full:
  The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL.AF4, AF4.MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and loss-of-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.


systematic_name: M1111
exact_source: Table AS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the set A (Fig. 5a): specific to cells expressing MLL-AF4 [GeneID=4297;4299] fusion protein alone.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M14833
exact_source: Table BS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the set B (Fig. 5a): specific signature shared by cells expressing either AF4-MLL or MLL-AF4 [GeneID=4299;4297] fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M9012
exact_source: Table BS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the set B (Fig. 5a): specific signature shared by cells expressing either AF4-MLL or MLL-AF4 [GeneID=4299;4297] fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M1113
exact_source: Table CS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the set C (Fig. 5a): specific to cells expressing AF4-MLL [GeneID=4299;4297] fusion protein alone.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M1115
exact_source: Table CS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the set C (Fig. 5a): specific to cells expressing AF4-MLL [GeneID=4299;4297] fusion protein alone.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M1801
exact_source: Table DS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the set D (Fig. 5a): specific signature shared by cells expressing MLL-AF4 [GeneID=4297;4299] alone and those expressing both MLL-AF4 and AF4-MLL fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M527
exact_source: Table DS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the set D (Fig. 5a): specific signature shared by cells expressing MLL-AF4 [GeneID=4297;4299] alone and those expressing both MLL-AF4 and AF4-MLL fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M11319
exact_source: Table ES
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the set E (Fig. 5a): specific signature shared by cells expressing either MLL-AF4 [GeneID=4297;4299] or AF4-MLL fusion proteins alone, and those expressing both fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M2039
exact_source: Table ES
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the set E (Fig. 5a): specific signature shared by cells expressing either MLL-AF4 [GeneID=4297;4299] or AF4-MLL fusion proteins alone, and those expressing both fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M588
exact_source: Table FS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regualted genes from the set F (Fig. 5a): specific signature shared by cells expressing AF4-MLL [GeneID=4299;4297] alone and those expressing both AF4-MLL and MLL-AF4 fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M11023
exact_source: Table GS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the set G (Fig. 5a): specific to cells expressing both MLL-AF4 [GeneID=4297;4299] and AF4-MLL fusion proteins.

description_full:
[cell repeats an earlier one in this file: 1437 characters]


systematic_name: M7919
exact_source: Table 4S: RhoAi > 1
source_species_code: MM
GEO_id: GSE5913
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in NIH3T3 cells (fibroblasts) transfrormed by expression of constitutively active (Q63L) form of RHOA [GeneID=387] off plasmid vector; their expression did NOT reverted completely after treatment with Y27632 [PubChem=123862], an inhibitor of ROCK proteins.

description_full:
[cell repeats an earlier one in this file: 1498 characters]


systematic_name: M366
exact_source: Table 2S: Fold change: TUvsWT > 1
source_species_code: MM
GEO_id: GSE2528
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the 324 genes identified by two analytical methods as changed in the mammary tumors induced by transgenic expression of ERBB2 [GeneID=2064].

description_full:
[cell repeats an earlier one in this file: 1973 characters]


systematic_name: M1122
exact_source: Table 1a: Co. vs PAP > 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in benign skin tumors (papilloma) induced by treatment with DMBA and TPA [PubChem=6001;4792] chemicals in the two stage skin carcinogenesis model.

description_full:
[cell repeats an earlier one in this file: 1495 characters]


systematic_name: M1126
exact_source: Table 1b: Co. vs SCC > 0
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in malignant skin tumors (squamous cell carcinoma, SCC) formed by treatment with DMBA and TPA [PubChem=6001;4792] in the two stage skin carcinogenesis model.

description_full:
[cell repeats an earlier one in this file: 1495 characters]


description_brief: Myb family target genes.
systematic_name: M1128
exact_source: Table 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Hematopoiesis, the process by which mature blood cells arise, is controlled by multiple transcription factors, which act in stage- and lineage-specific complexes. It is a major goal to elucidate the genes regulated by these transcription factors, in order to obtain a full understanding of the process and its malignant counterpart, leukemia. Myb family transcription factors play a central role in hematopoiesis. To identify new Myb family target genes, we have used an inducible dominant-negative protein for a subtraction cloning protocol in a model cell system (FDCP-Mix) with many characteristics of normal hematopoiesis. We present here a novel group of 29 validated Myb family target genes of diverse functions.


systematic_name: M1130
exact_source: Fig 2B
source_species_code: MM
GEO_id: GSE6453
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'TEB profile genes': down-regulated during pubertal mammary gland development specifically in the TEB (terminal end bud) structures.

description_full:
[cell repeats an earlier one in this file: 1251 characters]


systematic_name: M1131
exact_source: Table 1S: Chronic TPA > 1
source_species_code: MM
GEO_id: GSE5576
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated during skin tumor progression: epidermis treated with the carcinogen DMBA [PubChem=6001] followed by 20 weekly applications of the tumor promoter TPA [PubChem=4792], compared to the untreated skin.

description_full:
  Chemical induction of squamous tumors in the mouse skin induces multiple benign papillomas: high-frequency terminally benign low-risk papillomas and low-frequency high-risk papillomas, the putative precursor lesions to squamous cell carcinoma (SCC). We have compared the gene expression profile of twenty different early low- and high-risk papillomas with normal skin and SCC. Unsupervised clustering of 514 differentially expressed genes (P<0.001) showed that 9/10 high-risk papillomas clustered with SCC, while 1/10 clustered with low-risk papillomas, and this correlated with keratin markers of tumor progression. Prediction analysis for microarrays (PAM) identified 87 genes that distinguished the two papilloma classes, and a majority of these had a similar expression pattern in both high-risk papillomas and SCC. Additional classifier algorithms generated a gene list that correctly classified unknown benign tumors as low- or high-risk concordant with promotion protocol and keratin profiling. Reduced expression of immune function genes characterized the high-risk papillomas and SCC. Immunohistochemistry confirmed reduced T-cell number in high-risk papillomas, suggesting that reduced adaptive immunity defines papillomas that progress to SCC. These results demonstrate that murine premalignant lesions can be segregated into subgroups by gene expression patterns that correlate with risk for malignant conversion, and suggest a paradigm for generating diagnostic biomarkers for human premalignant lesions with unknown individual risk for malignant conversion.


systematic_name: M1132
exact_source: Table 1S: Chronic TPA < 1
source_species_code: MM
GEO_id: GSE5576
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated during skin tumor progression: epidermis treated with the carcinogen DMBA [PubChem=6001] followed by 20 weekly applications of the tumor promoter TPA [PubChem=4792], compared to the untreated skin.

description_full:
  Chemical induction of squamous tumors in the mouse skin induces multiple benign papillomas: high-frequency terminally benign low-risk papillomas and low-frequency high-risk papillomas, the putative precursor lesions to squamous cell carcinoma (SCC). We have compared the gene expression profile of twenty different early low- and high-risk papillomas with normal skin and SCC. Unsupervised clustering of 514 differentially expressed genes (P<0.001) showed that 9/10 high-risk papillomas clustered with SCC, while 1/10 clustered with low-risk papillomas, and this correlated with keratin markers of tumor progression. Prediction analysis for microarrays (PAM) identified 87 genes that distinguished the two papilloma classes, and a majority of these had a similar expression pattern in both high-risk papillomas and SCC. Additional classifier algorithms generated a gene list that correctly classified unknown benign tumors as low- or high-risk concordant with promotion protocol and keratin profiling. Reduced expression of immune function genes characterized the high-risk papillomas and SCC. Immunohistochemistry confirmed reduced T-cell number in high-risk papillomas, suggesting that reduced adaptive immunity defines papillomas that progress to SCC. These results demonstrate that murine premalignant lesions can be segregated into subgroups by gene expression patterns that correlate with risk for malignant conversion, and suggest a paradigm for generating diagnostic biomarkers for human premalignant lesions with unknown individual risk for malignant conversion.


systematic_name: M1150
exact_source: Table 1: TGFb-upregulated genes (smad4 dependent)
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Apoptotic genes dependent on SMAD4 [GeneID=4089] and up-regulated in AML12 cells (hepatocytes) after stimulation with TGFB1 [GeneID=7040].

description_full:
  Transforming growth factor-beta (TGFbeta)-activated signalling pathways can lead to apoptosis, growth arrest or promotion of malignant behaviour, dependent on cellular context. The molecular mechanisms involved in TGFbeta-induced apoptosis remain controversial; although changes in gene expression are thought to be pivotal to the process, several different candidate apoptotic initiators and mediators have been proposed. Smad4, a critical component of the TGFbeta-induced transcriptional machinery, is shown here to be essential for induction of apoptosis. Gene expression analysis identified the proapoptotic Bcl-2 family members, Bmf and Bim, as induced by TGFbeta, dependent on both Smad4 and p38 function and the generation of reactive oxygen species. TGFbeta-induced Bmf and Bim localize to cellular membranes implicated in apoptosis. Inhibition of the TGFbeta-induced expression of both these proteins together provides significant protection of cells from apoptosis. The TGFbeta-triggered cell death programme thus involves induction of multiple BH3-only proteins during the induction of apoptosis.


systematic_name: M1151
exact_source: Table 1: TGFb-downregulated genes (smad4 dependent)
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Apoptotic genes dependent on SMAD4 [GeneID=4089] and down-regulated in AML12 cells (hepatocytes) after stimulation with TGFB1 [GeneID=7040].

description_full:
  Transforming growth factor-beta (TGFbeta)-activated signalling pathways can lead to apoptosis, growth arrest or promotion of malignant behaviour, dependent on cellular context. The molecular mechanisms involved in TGFbeta-induced apoptosis remain controversial; although changes in gene expression are thought to be pivotal to the process, several different candidate apoptotic initiators and mediators have been proposed. Smad4, a critical component of the TGFbeta-induced transcriptional machinery, is shown here to be essential for induction of apoptosis. Gene expression analysis identified the proapoptotic Bcl-2 family members, Bmf and Bim, as induced by TGFbeta, dependent on both Smad4 and p38 function and the generation of reactive oxygen species. TGFbeta-induced Bmf and Bim localize to cellular membranes implicated in apoptosis. Inhibition of the TGFbeta-induced expression of both these proteins together provides significant protection of cells from apoptosis. The TGFbeta-triggered cell death programme thus involves induction of multiple BH3-only proteins during the induction of apoptosis.


systematic_name: M1152
exact_source: Table 1: TGFb-upregulated genes (p38 dependent)
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Apoptotic genes dependent on MAPK1 [GeneID=5594] and up-regulated in AML12 cells (hepatocytes) after stimulation with TGFB1 [GeneID=7040].

description_full:
  Transforming growth factor-beta (TGFbeta)-activated signalling pathways can lead to apoptosis, growth arrest or promotion of malignant behaviour, dependent on cellular context. The molecular mechanisms involved in TGFbeta-induced apoptosis remain controversial; although changes in gene expression are thought to be pivotal to the process, several different candidate apoptotic initiators and mediators have been proposed. Smad4, a critical component of the TGFbeta-induced transcriptional machinery, is shown here to be essential for induction of apoptosis. Gene expression analysis identified the proapoptotic Bcl-2 family members, Bmf and Bim, as induced by TGFbeta, dependent on both Smad4 and p38 function and the generation of reactive oxygen species. TGFbeta-induced Bmf and Bim localize to cellular membranes implicated in apoptosis. Inhibition of the TGFbeta-induced expression of both these proteins together provides significant protection of cells from apoptosis. The TGFbeta-triggered cell death programme thus involves induction of multiple BH3-only proteins during the induction of apoptosis.


systematic_name: M1154
exact_source: Table 1: TGFb-downregulated genes (p38 dependent)
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Apoptotic genes dependent on MAPK1 [GeneID=5594] and down-regulated in AML12 cells (hepatocytes) after stimulation with TGFB1 [GeneID=7040].

description_full:
[cell repeats an earlier one in this file: 1107 characters]


systematic_name: M1156
exact_source: Table 1S: induced by E2F1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MEF cells (embryonic fibroblast) at 16 h after serum stimulation and knockdown of E2F1 [GeneID=1869] by RNAi.

description_full:
  Functions encoded by single genes in lower organisms are often represented by multiple related genes in the mammalian genome. An example is the retinoblastoma and E2F families of proteins that regulate transcription during the cell cycle. Analysis of gene function using germline mutations is often confounded by overlapping function resulting in compensation. Indeed, in cells deleted of the E2F1 or E2F3 genes, there is an increase in the expression of the other family member. To avoid complications of compensatory effects, we have used small-interfering RNAs that target individual E2F proteins to generate a temporary loss of E2F function. We find that both E2F1 and E2F3 are required for cells to enter the S phase from a quiescent state, whereas only E2F3 is necessary for the S phase in growing cells. We also find that the acute loss of E2F3 activity affects the expression of genes encoding DNA replication and mitotic activities, whereas loss of E2F1 affects a limited number of genes that are distinct from those regulated by E2F3. We conclude that the long-term loss of E2F activity does lead to compensation by other family members and that the analysis of acute loss of function reveals specific and distinct roles for these proteins.


systematic_name: M802
exact_source: Table 3S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected gradually up-regulated genes whose expression profile follows that of HBZ [GeneID=3050] in the TLX1 [GeneID=3195] Tet On iEBHX15-4 cells (pro-erythroblasts).

description_full:
  Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.


systematic_name: M7999
exact_source: Table 4S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected gradually up-regulated genes whose expression profile follows that of HEMGN [GeneID=55363] in the TLX1 [GeneID=3195] Tet On iEBHX15-4 cells (pro-erythroblasts).

description_full:
[cell repeats an earlier one in this file: 1610 characters]


systematic_name: M15638
exact_source: Table 5S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected genes whose expression profile follows that of APOBEC2 [GeneID=10930] in the TLX1 [GeneID=3195] Tet On iEBHX15-4 cells (pro-erythroblasts).

description_full:
[cell repeats an earlier one in this file: 1610 characters]


systematic_name: M1854
exact_source: Table 6S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected genes down-regulated in the TLX1 [GeneID=3195] Tet On iEBHX15-4 cells (pro-erythroblasts) at 6 h time point.

description_full:
[cell repeats an earlier one in this file: 1610 characters]


systematic_name: M4389
exact_source: Table 7S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Selected genes down-regulated in the TLX1 [GeneID=3195] Tet On iEBHX15-4 cells (pro-erythroblasts) at 12 h time point.

description_full:
[cell repeats an earlier one in this file: 1610 characters]


systematic_name: M1167
exact_source: Table 2: clusters 2.1 and 3.1-4
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Selected genes up-regulated during progression through benign to malignant skin tumors formed by treatment with DMBA and TPA [PubChem=6001;4792] chemicals in the two stage skin carcinogenesis model.

description_full:
[cell repeats an earlier one in this file: 1495 characters]


systematic_name: M15659
exact_source: Supplementary Table A: cluster 5
source_species_code: MM
GEO_id: GSE2118
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 5: early responding genes activated in ATM [GeneID=472] deficient but not in the wild type tissues.

description_full:
[cell repeats an earlier one in this file: 1616 characters]


description_brief: Genes up-regulated in cells expressing MEN1 [GeneID=4221].
systematic_name: M1182
exact_source: Table 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Menin is encoded by the tumor suppressor gene MEN1 that is mutated in patients with an inherited tumor syndrome, multiple endocrine neoplasia type 1 (MEN1). Although menin is a nuclear protein and directly binds to DNA through its nuclear localization signals (NLSs), the precise role for each of the NLSs in nuclear translocation and gene expression remains to be elucidated. Here, we show that point mutations in three individual NLSs, NLS1, NLS2, and a novel accessory NLS, NLSa, do not block nuclear translocation, but compromise the ability of menin to repress expression of the endogenous insulin-like growth factor binding protein-2 (IGFBP-2) gene. This repression is not released by an inhibitor of histone deacetylases. Although subtle mutations in menin NLSs do not affect menin association with chromatin, they abolish menin binding to the IGFBP-2 promoter in vivo. Furthermore, each of the NLSs is also crucial for menin-mediated induction of caspase 8 expression. Together, these results suggest that menin may act as a scaffold protein in coordinating activation and repression of gene transcription and that its NLSs play a more important role in controlling gene transcription than merely targeting menin into the nucleus.


systematic_name: M1197
exact_source: Suppl. Data: Cluster 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 1: genes whose up-regulation peaked one day after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].

description_full:
  Activated forms of Ras family members are prevalent in many cancers where Ras mutants transduce signals essential for transformation, angiogenesis, invasion and metastasis. As a cancer progression model, we used NIH3T3 cells to explore the mechanism of Ras-induced tumorigenesis. Ras family mutants H-RasV12 and Rit79L strongly induced foci formation, while Rho family mutants RhoA-QL, Rac1-QL and Cdc42-QL were less effective. A comparison of downstream transcriptional targets of Ras and Rho family members using a 26 383 element cDNA microarray revealed that the osteopontin (OPN) gene exhibited the best correlation between magnitude of gene expression change and level of foci formation (r=0.96, P<0.001). In association with H-RasV12- and Rit79L-mediated transformation, foci secreted OPN protein and upregulated the OPN receptor CD44, suggesting the novel initiation of an aberrant OPN-CD44-Rac autocrine pathway. In support of this were the following observations. First, RGD-deficient OPN protein-binding activity was present in H-RasV12-transformed cells but not in control cells, and binding activity was inhibited by the CD44 blocking antibody. Second, foci formation, cell invasion and Rac activity were induced by H-RasV12 and inhibited by the CD44 blocking antibody. Third, foci formation by H-RasV12 was substantially reduced by a short interfering RNA (siRNA) specifically targeting OPN expression for knockdown. Fourth, H-RasV12-mediated transformation was not blocked by the GRGDS peptide, suggesting that OPN effects were not mediated by the integrins. Lastly, OPN knockdown affected the downstream expression of 160 '2nd tier' genes, and at least a subset of these genes appears to be involved in transformation. Indeed, four genes were selected for knockdown, each resulting in a disruption of foci formation and/or invasion. These results underscore the role of aberrant autocrine signaling and transcriptional networking during tumorigenesis.


systematic_name: M1198
exact_source: Suppl. Data: Cluster 3
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 3: genes whose up-regulation peaked 3 days after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].

description_full:
  Activated forms of Ras family members are prevalent in many cancers where Ras mutants transduce signals essential for transformation, angiogenesis, invasion and metastasis. As a cancer progression model, we used NIH3T3 cells to explore the mechanism of Ras-induced tumorigenesis. Ras family mutants H-RasV12 and Rit79L strongly induced foci formation, while Rho family mutants RhoA-QL, Rac1-QL and Cdc42-QL were less effective. A comparison of downstream transcriptional targets of Ras and Rho family members using a 26 383 element cDNA microarray revealed that the osteopontin (OPN) gene exhibited the best correlation between magnitude of gene expression change and level of foci formation (r=0.96, P<0.001). In association with H-RasV12- and Rit79L-mediated transformation, foci secreted OPN protein and upregulated the OPN receptor CD44, suggesting the novel initiation of an aberrant OPN-CD44-Rac autocrine pathway. In support of this were the following observations. First, RGD-deficient OPN protein-binding activity was present in H-RasV12-transformed cells but not in control cells, and binding activity was inhibited by the CD44 blocking antibody. Second, foci formation, cell invasion and Rac activity were induced by H-RasV12 and inhibited by the CD44 blocking antibody. Third, foci formation by H-RasV12 was substantially reduced by a short interfering RNA (siRNA) specifically targeting OPN expression for knockdown. Fourth, H-RasV12-mediated transformation was not blocked by the GRGDS peptide, suggesting that OPN effects were not mediated by the integrins. Lastly, OPN knockdown affected the downstream expression of 160 '2nd tier' genes, and at least a subset of these genes appears to be involved in transformation. Indeed, four genes were selected for knockdown, each resulting in a disruption of foci formation and/or invasion. These results underscore the role of aberrant autocrine signaling and transcriptional networking during tumorigenesis.


systematic_name: M1199
exact_source: Suppl. Data: Cluster 4
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 4: genes whose up-regulation peaked 4 days after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].

description_full:
  Activated forms of Ras family members are prevalent in many cancers where Ras mutants transduce signals essential for transformation, angiogenesis, invasion and metastasis. As a cancer progression model, we used NIH3T3 cells to explore the mechanism of Ras-induced tumorigenesis. Ras family mutants H-RasV12 and Rit79L strongly induced foci formation, while Rho family mutants RhoA-QL, Rac1-QL and Cdc42-QL were less effective. A comparison of downstream transcriptional targets of Ras and Rho family members using a 26 383 element cDNA microarray revealed that the osteopontin (OPN) gene exhibited the best correlation between magnitude of gene expression change and level of foci formation (r=0.96, P<0.001). In association with H-RasV12- and Rit79L-mediated transformation, foci secreted OPN protein and upregulated the OPN receptor CD44, suggesting the novel initiation of an aberrant OPN-CD44-Rac autocrine pathway. In support of this were the following observations. First, RGD-deficient OPN protein-binding activity was present in H-RasV12-transformed cells but not in control cells, and binding activity was inhibited by the CD44 blocking antibody. Second, foci formation, cell invasion and Rac activity were induced by H-RasV12 and inhibited by the CD44 blocking antibody. Third, foci formation by H-RasV12 was substantially reduced by a short interfering RNA (siRNA) specifically targeting OPN expression for knockdown. Fourth, H-RasV12-mediated transformation was not blocked by the GRGDS peptide, suggesting that OPN effects were not mediated by the integrins. Lastly, OPN knockdown affected the downstream expression of 160 '2nd tier' genes, and at least a subset of these genes appears to be involved in transformation. Indeed, four genes were selected for knockdown, each resulting in a disruption of foci formation and/or invasion. These results underscore the role of aberrant autocrine signaling and transcriptional networking during tumorigenesis.


systematic_name: M1201
exact_source: Suppl. Data: Cluster 5
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 5: genes whose up-regulation peaked 5 days after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].

description_full:
[cell repeats an earlier one in this file: 1966 characters]


systematic_name: M1202
exact_source: Suppl. Data: Cluster 6
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 6:  genes exhibiting prolonged up-regulation (>72 h) after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].

description_full:
[cell repeats an earlier one in this file: 1966 characters]


systematic_name: M1203
exact_source: Suppl. Data: Cluster 7
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 7: genes down-regulated early (within 24 h) after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].

description_full:
[cell repeats an earlier one in this file: 1966 characters]


systematic_name: M1204
exact_source: Suppl. Data: Cluster 8
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cluster 8: genes showing sustained pattern of down-regulation after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].

description_full:
[cell repeats an earlier one in this file: 1966 characters]


systematic_name: M1218
exact_source: Table 2a
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in hepatocellular carcinoma (HCC) developed by transgenic mice overexpressing a secretable form of EGF [GeneID=1950] in liver.

description_full:
  Epidermal growth factor is an important mitogen for hepatocytes. Its overexpression promotes hepatocellular carcinogenesis. To identify the network of genes regulated through EGF, we investigated the liver transcriptome during various stages of hepatocarcinogenesis in EGF2B transgenic mice. Targeted overexpression of IgEGF induced distinct hepatocellular lesions and eventually solid tumours at the age of 6-8 months, as evidenced by histopathology. We used the murine MG U74Av2 oligonucleotide microarrays to identify transcript signatures in 12 tumours of small (n=5, pooled), medium (n=4) and large sizes (n=3), and compared the findings with three nontumorous transgenic livers and four control livers. Global gene expression analysis at successive stages of carcinogenesis revealed hallmarks linked to tumour size. A comparison of gene expression profiles of nontumorous transgenic liver versus control liver provided insight into the initial events predisposing liver cells to malignant transformation, and we found overexpression of c-fos, eps-15, TGIF, IGFBP1, Alcam, ets-2 and repression of Gas-1 as distinct events. Further, when gene expression profiles of small manifested tumours were compared with nontumorous transgenic liver, additional changes were obvious and included overexpression of junB, Id-1, minopontin, villin, claudin-7, RR M2, p34cdc2, cyclinD1 and cyclinB1 among others. These genes are therefore strongly associated with tumour formation. Our study provided new information on the tumour stage-dependent network of EGF-regulated genes, and we identified candidate genes linked to tumorigenes and progression of disease.


systematic_name: M1238
exact_source: Table 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes hypermethylated in at least one of the lymphoma tumors of transgenic mice overexpressing TCL1 [GeneID=8115] in germinal center B lymphocytes.

description_full:
  Most human lymphomas originate from transformed germinal center (GC) B lymphocytes. While activating mutations and translocations of MYC, BCL2 and BCL6 promote specific GC lymphoma subtypes, other genetic and epigenetic modifications that contribute to malignant progression in the GC remain poorly defined. Recently, aberrant expression of the TCL1 proto-oncogene was identified in major GC lymphoma subtypes. TCL1 transgenic mice offer unique models of both aggressive GC and marginal zone B-cell lymphomas, further supporting a role for TCL1 in B-cell transformation. Here, restriction landmark genomic scanning was employed to discover tumor-associated epigenetic alterations in malignant GC and marginal zone B-cells in TCL1 transgenic mice. Multiple genes were identified that underwent DNA hypermethylation and decreased expression in TCL1 transgenic tumors. Further, we identified a secreted isoform of EPHA7, a member of the Eph family of receptor tyrosine kinases that are able to influence tumor invasiveness, metastasis and neovascularization. EPHA7 was hypermethylated and repressed in both mouse and human GC B-cell non-Hodgkin lymphomas, with the potential to influence tumor progression and spread. These data provide the first set of hypermethylated genes with the potential to complement TCL1-mediated GC B-cell transformation and spread.


systematic_name: M1240
exact_source: Table 1
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in early vs late brain tumors induced by retroviral delivery of PDGFB [GeneID=5155].

description_full:
[cell repeats an earlier one in this file: 1456 characters]


systematic_name: M1243
exact_source: Table 1
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by telomere shortening due to the knockout of TERC [GeneID=7012] in the presence of chronic liver damage.

description_full:
  Telomere shortening limits the regenerative capacity of cells during aging and chronic disease but at the same time inhibits tumor progression, and it has yet to be determined which of these mechanisms is dominantly affecting organismal survival. Here we show that telomere shortening in telomerase knockout (mTERC-/-) mice in combination with chronic liver damage significantly reduced organismal survival even though telomere shortening strongly inhibited liver tumor formation. Decreased survival induced by telomere shortening correlated with an imbalance between liver cell proliferation and liver cell apoptosis. Specific changes in gene expression were associated with telomere shortening and chronic liver damage and these gene expression changes were partially reversed by adenovirus mediated telomerase gene delivery. This study gives experimental evidence that the negative impact of telomere shortening on organ homeostasis and organismal survival can surpass the beneficial effects of telomere shortening on suppression of tumor growth in the setting of chronic organ damage.


systematic_name: M1263
exact_source: Table 2: set B
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the mouse lung cancer model and which reverted to normal levels upon treatment with bexarotene [PubChem=82146].

description_full:
  Bexarotene (Targretin), is a synthetic high-affinity RXR receptor agonist with limited affinity for RAR receptors. Bexarotene has shown efficacy in a phase I/II trial of non-small-cell lung cancers. However, the chemopreventive efficacy of bexarotene has not been determined in mouse lung cancer models. In this study, we have investigated the ability of bexarotene to inhibit lung tumor progression in the mutant A/J mouse models with genetic alterations in p53 or K-ras, two of the most commonly altered genes in human lung tumorigenesis. Mice were administered vinyl carbamate (VC), a carcinogen, by a single intraperitoneal injection (i.p.) at 6 weeks of age. Bexarotene was given by gavage starting at 16 weeks after VC and was continued for 12 weeks. Although all mice developed lung tumors, only 7% of lung tumors were adenocarcinomas in wild-type mice, whereas 22 and 26% of lung tumors were adenocarcinomas in p53 transgenic or K-ras heterozygous deficient mice. Bexarotene inhibited both tumor multiplicity and tumor volume in mice of all three genotypes. Furthermore, bexarotene reduced the progression of adenoma to adenocarcinoma by approximately 50% in both p53(wt/wt)K-ras(ko/wt) and p53(wt/wt)K-ras(wt/wt) mice. Thus, bexarotene appears to be an effective preventive agent against lung tumor growth and progression.


systematic_name: M1264
exact_source: Table 2: set A
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the mouse lung cancer model and which reverted to normal levels upon treatment with bexarotene [PubChem=82146].

description_full:
  Bexarotene (Targretin), is a synthetic high-affinity RXR receptor agonist with limited affinity for RAR receptors. Bexarotene has shown efficacy in a phase I/II trial of non-small-cell lung cancers. However, the chemopreventive efficacy of bexarotene has not been determined in mouse lung cancer models. In this study, we have investigated the ability of bexarotene to inhibit lung tumor progression in the mutant A/J mouse models with genetic alterations in p53 or K-ras, two of the most commonly altered genes in human lung tumorigenesis. Mice were administered vinyl carbamate (VC), a carcinogen, by a single intraperitoneal injection (i.p.) at 6 weeks of age. Bexarotene was given by gavage starting at 16 weeks after VC and was continued for 12 weeks. Although all mice developed lung tumors, only 7% of lung tumors were adenocarcinomas in wild-type mice, whereas 22 and 26% of lung tumors were adenocarcinomas in p53 transgenic or K-ras heterozygous deficient mice. Bexarotene inhibited both tumor multiplicity and tumor volume in mice of all three genotypes. Furthermore, bexarotene reduced the progression of adenoma to adenocarcinoma by approximately 50% in both p53(wt/wt)K-ras(ko/wt) and p53(wt/wt)K-ras(wt/wt) mice. Thus, bexarotene appears to be an effective preventive agent against lung tumor growth and progression.


systematic_name: M1267
exact_source: Supplementary Data 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in pubertal mammary glands compared to mammary glands from other developmental stages.

description_full:
  Expression microarray analysis identified CITED1 among a group of genes specifically upregulated in the pubertal mouse mammary gland. At puberty, CITED1 localizes to the luminal epithelial cell population of the mammary ducts and the body cells of the terminal end buds. Generation of CITED1 gene knockout mice showed that homozygous null mutants exhibit retarded mammary ductal growth at puberty and, in addition, dilated ductal structures with a lack of spatial restriction of the subtending branches. Analysis of CITED1 homozygous null and heterozygous null mammary gland gene expression using microarrays suggested that the mammary-specific phenotype seen in the homozygous null females is due to a disturbance in the transcription of a number of key mediators of pubertal ductal morphogenesis. These include estrogen and TGFbeta responsive genes, such as the EGFR/ErbB2 ligand, amphiregulin, whose transcription we suggest is directly or indirectly regulated by CITED1.


systematic_name: M1275
exact_source: Table 2S
source_species_code: MM
GEO_id: GSE2127
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster PAM2: genes up-regulated in hepatocellular carcinoma (HCC) vs normal liver tissue from mice deficient for TXNIP [GeneID=10628].

description_full:
  The molecular pathogenesis and the genetic aberrations that lead to the progression of hepatocellular carcinoma (HCC) are largely unknown. Here, we demonstrate that the thioredoxin interacting protein (Txnip) gene is a candidate tumor suppressor gene in vivo. We previously showed that the recombinant inbred congenic strain HcB-19 has a spontaneous mutation of the Txnip gene, and we now show that the strain has dramatically increased incidence of HCC, and that the HCC cosegregates with the Txnip mutation. Approximately 40% of the Txnip-deficient mice developed hepatic tumors with an increased prevalence in male mice. Visible tumors develop as early as 8 months of age. Histological analysis confirmed the morphology of HCC in the Txnip-deficient mice. Molecular markers of HCC, alpha-fetoprotein and p53, were increased in tumors of Txnip-deficient mice. The upregulation of p53 preceded tumor development; however, bromodeoxyuridine (BrdU) labeling of normal hepatic tissue of Txnip-deficient mice did not reveal increased cell proliferation. Finally, microarray analyses of tumor, non-tumor adjacent, and normal tissue of Txnip-deficient mice highlighted the genetic differences leading to the predisposition and onset of HCC. Our findings suggest that Txnip deficiency is sufficient to initiate HCC and suggest novel mechanisms in hepatocarcinogenesis.


systematic_name: M1277
exact_source: Table 3S
source_species_code: MM
GEO_id: GSE2127
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster PAM3: genes most highly up-regulated in hepatocellular carcinoma (HCC) vs normal liver tissue from mice deficient for TXNIP [GeneID=10628].

description_full:
[cell repeats an earlier one in this file: 1362 characters]


systematic_name: M1281
exact_source: Table 5S
source_species_code: MM
GEO_id: GSE2127
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster PAM5: genes changed exclusively in hepatocellular carcinoma (HCC) samples from 27 month old mice deficient for TXNIP [GeneID=10628].

description_full:
[cell repeats an earlier one in this file: 1362 characters]


systematic_name: M1284
exact_source: Table 6S
source_species_code: MM
GEO_id: GSE2127
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Cluster PAM6: genes changed exclusively in normal liver tissue adjacent to hepatocellular carcinoma (HCC) from mice deficient for TXNIP [GeneID=10628].

description_full:
[cell repeats an earlier one in this file: 1362 characters]


description_brief: These genes form a a network that controls specific processes downstream of PDGF signaling.
systematic_name: M1285
exact_source: Table 1S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Growth factor signaling leads to the induction or repression of immediate early genes, but how these genes act collectively as effectors of downstream processes remains unresolved. We have used gene trap-coupled microarray analysis to identify and mutate multiple platelet-derived growth factor (PDGF) intermediate early genes in mice. Mutations in these genes lead to a high frequency of phenotypes that affect the same cell types and processes as those controlled by the PDGF pathway. We conclude that these genes form a network that controls specific processes downstream of PDGF signaling.


systematic_name: M7084
exact_source: Table 3S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in LSK cells (bone marrow) as a function of a QTL for the size of hematopoietic stem cell (HSC) population: comparison of congenic B.D. chr3 (BD, large HSC size) vs parental B6 strain (tiny HSC size).

description_full:
  We mapped quantitative trait loci that accounted for the variation in hematopoietic stem cell (HSC) numbers between young adult C57BL/6 (B6) and DBA/2 (D2) mice. In reciprocal chromosome 3 congenic mice, introgressed D2 alleles increased HSC numbers owing to enhanced proliferation and self-renewal and reduced apoptosis, whereas B6 alleles had the opposite effects. Using oligonucleotide arrays, real-time PCR and protein blots, we identified latexin (Lxn), a gene whose differential transcription and expression was associated with the allelic differences. Expression was inversely correlated with the number of HSCs; therefore, ectopic expression of Lxn using a retroviral vector decreased stem cell population size. We identified clusters of SNPs upstream of the Lxn transcriptional start site, at least two of which are associated with potential binding sites for transcription factors regulating stem cells. Thus, promoter polymorphisms between the B6 and D2 alleles may affect Lxn gene expression and consequently influence the population size of hematopoietic stem cells.


systematic_name: M870
exact_source: Table 3S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in LSK cells (bone marrow) as a function of a QTL for the size of hematopoietic stem cell (HSC) population: comparison of congenic B.D. chr3 (BD, large HSC size) vs parental B6 strain (tiny HSC size).

description_full:
  We mapped quantitative trait loci that accounted for the variation in hematopoietic stem cell (HSC) numbers between young adult C57BL/6 (B6) and DBA/2 (D2) mice. In reciprocal chromosome 3 congenic mice, introgressed D2 alleles increased HSC numbers owing to enhanced proliferation and self-renewal and reduced apoptosis, whereas B6 alleles had the opposite effects. Using oligonucleotide arrays, real-time PCR and protein blots, we identified latexin (Lxn), a gene whose differential transcription and expression was associated with the allelic differences. Expression was inversely correlated with the number of HSCs; therefore, ectopic expression of Lxn using a retroviral vector decreased stem cell population size. We identified clusters of SNPs upstream of the Lxn transcriptional start site, at least two of which are associated with potential binding sites for transcription factors regulating stem cells. Thus, promoter polymorphisms between the B6 and D2 alleles may affect Lxn gene expression and consequently influence the population size of hematopoietic stem cells.


systematic_name: M10245
exact_source: Table 4S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in LSK cells (bone marrow) as a function of a QTL for the size of hematopoietic stem cell (HSC) population: comparison of congenic D.B. Chr 3 (DB, small HSC population) vs parental D2 strain (huge HSC population).

description_full:
  We mapped quantitative trait loci that accounted for the variation in hematopoietic stem cell (HSC) numbers between young adult C57BL/6 (B6) and DBA/2 (D2) mice. In reciprocal chromosome 3 congenic mice, introgressed D2 alleles increased HSC numbers owing to enhanced proliferation and self-renewal and reduced apoptosis, whereas B6 alleles had the opposite effects. Using oligonucleotide arrays, real-time PCR and protein blots, we identified latexin (Lxn), a gene whose differential transcription and expression was associated with the allelic differences. Expression was inversely correlated with the number of HSCs; therefore, ectopic expression of Lxn using a retroviral vector decreased stem cell population size. We identified clusters of SNPs upstream of the Lxn transcriptional start site, at least two of which are associated with potential binding sites for transcription factors regulating stem cells. Thus, promoter polymorphisms between the B6 and D2 alleles may affect Lxn gene expression and consequently influence the population size of hematopoietic stem cells.


systematic_name: M19655
exact_source: Table 4S
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in LSK cells (bone marrow) as a function of a QTL for the size of hematopoietic stem cell (HSC) population: comparison of congenic D.B. Chr 3 (DB, small HSC population) vs parental D2 strain (huge HSC population).

description_full:
[cell repeats an earlier one in this file: 1079 characters]


systematic_name: M1289
exact_source: Table 1S: FC > 0
source_species_code: MM
GEO_id: GSE7342
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in fetal liver (days E13.5 and E15.5) samples from embryo-specific Cre-lox knockout of MAPK14 [GeneID=1432].

description_full:
  The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.


systematic_name: M1399
exact_source: Table 2S: FC > 2
source_species_code: MM
GEO_id: GSE9012
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Retinoic acid-responsive genes up-regulated in hepatocellular carcinoma (HCC) samples of TRIM24 [GeneID=8805] knockout mice.

description_full:
  Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1alpha) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmacological approaches, we show that inhibition of retinoic acid signaling markedly reduces hepatocyte proliferation in Trim24-/- mice. We further show that deletion of a single retinoic acid receptor alpha (Rara) allele in a Trim24-null background suppresses HCC development and restores wild-type expression of retinoic acid-responsive genes in the liver, thus demonstrating that in this genetic background Rara expresses an oncogenic activity correlating with a dysregulation of the retinoic acid signaling pathway. Our results not only provide genetic evidence that Trim24 and Rara co-regulate hepatocarcinogenesis in an antagonistic manner but also suggest that aberrant activation of Rara is deleterious to liver homeostasis.


systematic_name: M5125
exact_source: Table 2S: FC < 1
source_species_code: MM
GEO_id: GSE9012
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Retinoic acid-responsive genes down-regulated in hepatocellular carcinoma (HCC) samples of TRIM24 [GeneID=8805] knockout mice.

description_full:
  Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1alpha) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmacological approaches, we show that inhibition of retinoic acid signaling markedly reduces hepatocyte proliferation in Trim24-/- mice. We further show that deletion of a single retinoic acid receptor alpha (Rara) allele in a Trim24-null background suppresses HCC development and restores wild-type expression of retinoic acid-responsive genes in the liver, thus demonstrating that in this genetic background Rara expresses an oncogenic activity correlating with a dysregulation of the retinoic acid signaling pathway. Our results not only provide genetic evidence that Trim24 and Rara co-regulate hepatocarcinogenesis in an antagonistic manner but also suggest that aberrant activation of Rara is deleterious to liver homeostasis.


systematic_name: M1295
exact_source: Table 4
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Stemness-related genes changed in A17 carcinomas (MTC, mesenchymal tumor cells) compared with the mesenchymal stem cells (MSC).

description_full:
  Tumor microenvironment in carcinomas recruits mesenchymal cells with an abnormal proangiogenic and invasive phenotype. It is not clear whether mesenchymal tumor cells (MTCs) derive from the activation of mature fibroblasts or from their stem cell precursors. However, stromal cell activation in tumors resembles in several aspects the mesenchymal rearrangement which normally occurs during reparative processes such as wound healing. Mesenchymal stem cells (MSCs) play a crucial role in developmental and reparative processes and have extraordinary proangiogenic potential, on the basis of which they are thought to show great promise for the treatment of ischemic disorders. Here, we show that MTCs have proangiogenic potential and that they share the transcriptional expression of the best-known proangiogenic factors with MSCs. We also found that MTCs and MSCs have the same molecular signature for stemness-related genes, and that when co-implanted with cancer cells in syngeneic animals MSCs determine early tumor appearance, probably by favoring the angiogenic switch. Our data (1) reveal crucial aspects of the proangiogenic phenotype of MTCs, (2) strongly suggest their stem origin and (3) signal the risk of therapeutic use of MSCs in tumor-promoting conditions.


systematic_name: M1298
exact_source: Table 1S: Fold Change > 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in SEND cells (skin endothelium) at normal oxygen (normoxia) conditions after knockdown of ELK3 [GeneID=2004] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1306
exact_source: Table 3S: Fold Change > 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in SEND cells (skin endothelium) at normal oxygen (normoxia) conditions after knockdown of HIF1A [GeneID=3091] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


systematic_name: M1313
exact_source: Table 5S: FC siNetH / FC siNetN > 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes specifically up-regulated in SEND cells (skin endothelium) at hypoxia after knockdown of ELK3 [GeneID=2004] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1304 characters]


description_brief: Genes up-regulated in 10T1/2 cells (multipotent mesoderma) by expression of SHH [GeneID=6469].
systematic_name: M1320
exact_source: Table AS
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Aberrant regulation of signalling mechanisms that normally orchestrate embryonic development, such as the Hedgehog, Wnt and Notch pathways, is a common feature of tumorigenesis. In order to better understand the neoplastic events mediated by Hedgehog signalling, we identified over 200 genes regulated by Sonic Hedgehog in multipotent mesodermal cells. Widespread crosstalk with other developmental signalling pathways is evident, suggesting a complex network of interactions that challenges the often over-simplistic representation of these pathways as simple linear entities. Hes1, a principal effector of the Notch pathway, was found to be a target of Sonic Hedgehog in both C3H/10T1/2 mesodermal and MNS70 neural cells. Desert Hedgehog also elicited a strong Hes1 response. While Smoothened function was found necessary for upregulation of Hes1 in response to Sonic Hedgehog, the mechanism does not require gamma-secretase-mediated cleavage of Notch receptors, and appears to involve transcription factors other than RBP-Jkappa. Thus, we have defined a novel mechanism for Hes1 regulation in stem-like cells that is independent of canonical Notch signalling.


systematic_name: M1334
exact_source: Table 1
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in salivary, thyroid and mammary gland carcinomas developed in transgenic mice carrying RET [GeneID=5979] allele with the MEN2A mutation (C634R).

description_full:
  Germline mutations in the RET tyrosine kinase gene are responsible for the development of multiple endocrine neoplasia 2A and 2B (MEN2A and MEN2B). However, knowledge of the fundamental principles that determine the mutant RET-mediated signaling remains elusive. Here, we report increased expression of mitogen-activated protein kinase phosphatase-2 (MKP-2) in carcinomas developed in transgenic mice carrying RET with the MEN2A mutation (RET-MEN2A). The expression of MKP-2 was not only induced by RET-MEN2A or RET-MEN2B mutant proteins but also by the activation of endogenous RET by its ligand, glial cell line-derived neurotrophic factor (GDNF). MKP-2 expression was also evident in the MKK-f cell line, which was established from a mammary tumor developed in a RET-MEN2A transgenic mouse. Inhibition of MKP-2 attenuated the in vitro and in vivo proliferation of MKK-f cells, which was mediated by the suppression of cyclin B1 expression. Furthermore, we found that MKP-2 is highly expressed in medullary thyroid carcinomas derived from MEN2A patients. These findings suggest that the increased expression of MKP-2 may play a crucial role in oncogenic signaling downstream of mutant RET, leading to deregulation of cell cycle.


description_brief: Angiogenic genes up-regulated in hepatocytes after knockout of VHL and HIF2A [GeneID=7428;2034].
systematic_name: M1336
exact_source: Fig 2b: red in B & C vs A
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  The von Hippel-Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix-loop-helix transcription factors, which mediate the hypoxic induction of angiogenic growth factors such as vascular endothelial growth factor. Loss of pVHL function results in constitutive activation of HIF-1 and HIF-2 and is associated with the development of highly vascularized tumors in multiple organs. We have used a conditional gene-targeting approach to investigate the relative contributions of HIF-1 and HIF-2 to VHL-associated vascular tumorigenesis in a mouse model of liver hemangiomas. Here we demonstrate genetically that conditional inactivation of HIF-2alpha suppressed the development of VHL-associated liver hemangiomas and that angiogenic gene expression in hepatocytes is predominantly regulated by HIF-2 and not by HIF-1. These findings suggest that HIF-2 is the dominant HIF in the pathogenesis of VHL-associated vascular tumors and that pharmacologic targeting of HIF-2 may be an effective strategy for their treatment.


systematic_name: M11756
exact_source: Table 1
source_species_code: MM
GEO_id: GSE11732
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Common target genes up-regulated by all three Runx family members (RUNX1, RUNX2, and RUNX3 [GeneID=861;860;864]) in MEF cells (embryonic fibroblasts).

description_full:
  The Runx genes are important in development and cancer, where they can act either as oncogenes or tumour suppressors. We compared the effects of ectopic Runx expression in established fibroblasts, where all three genes produce an indistinguishable phenotype entailing epithelioid morphology and increased cell survival under stress conditions. Gene array analysis revealed a strongly overlapping transcriptional signature, with no examples of opposing regulation of the same target gene. A common set of 50 highly regulated genes was identified after further filtering on regulation by inducible RUNX1-ER. This set revealed a strong bias toward genes with annotated roles in cancer and development, and a preponderance of targets encoding extracellular or surface proteins, reflecting the marked effects of Runx on cell adhesion. Furthermore, in silico prediction of resistance to glucocorticoid growth inhibition was confirmed in fibroblasts and lymphoid cells expressing ectopic Runx. The effects of fibroblast expression of common RUNX1 fusion oncoproteins (RUNX1-ETO, TEL-RUNX1 and CBFB-MYH11) were also tested. Although two direct Runx activation target genes were repressed (Ncam1 and Rgc32), the fusion proteins appeared to disrupt the regulation of downregulated targets (Cebpd, Id2 and Rgs2) rather than impose constitutive repression. These results elucidate the oncogenic potential of the Runx family and reveal novel targets for therapeutic inhibition.


systematic_name: M4303
exact_source: Table 1
source_species_code: MM
GEO_id: GSE11732
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Common target genes down-regulated by all three Runx family members (RUNX1, RUNX2, and RUNX3 [GeneID=861;860;864]) in MEF cells (embryonic fibroblasts).

description_full:
  The Runx genes are important in development and cancer, where they can act either as oncogenes or tumour suppressors. We compared the effects of ectopic Runx expression in established fibroblasts, where all three genes produce an indistinguishable phenotype entailing epithelioid morphology and increased cell survival under stress conditions. Gene array analysis revealed a strongly overlapping transcriptional signature, with no examples of opposing regulation of the same target gene. A common set of 50 highly regulated genes was identified after further filtering on regulation by inducible RUNX1-ER. This set revealed a strong bias toward genes with annotated roles in cancer and development, and a preponderance of targets encoding extracellular or surface proteins, reflecting the marked effects of Runx on cell adhesion. Furthermore, in silico prediction of resistance to glucocorticoid growth inhibition was confirmed in fibroblasts and lymphoid cells expressing ectopic Runx. The effects of fibroblast expression of common RUNX1 fusion oncoproteins (RUNX1-ETO, TEL-RUNX1 and CBFB-MYH11) were also tested. Although two direct Runx activation target genes were repressed (Ncam1 and Rgc32), the fusion proteins appeared to disrupt the regulation of downregulated targets (Cebpd, Id2 and Rgs2) rather than impose constitutive repression. These results elucidate the oncogenic potential of the Runx family and reveal novel targets for therapeutic inhibition.


systematic_name: M1338
exact_source: Table 1
source_species_code: MM
GEO_id: GSE9651
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes commonly up-regulated in both non-tumorous and tumorous liver tissues of PARK2 [GeneID=5071] knockout mice.

description_full:
  The parkin was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism. Deregulation of the parkin gene, however, has been observed in various human cancers, suggesting that the parkin gene may be important in tumorigenesis. To gain insight into the physiologic role of parkin, we generated parkin-/- mice lacking exon 3 of the parkin gene. We demonstrated here that parkin-/- mice had enhanced hepatocyte proliferation and developed macroscopic hepatic tumors with the characteristics of hepatocellular carcinoma. Microarray analyses revealed that parkin deficiency caused the alteration of gene expression profiles in the liver. Among them, endogenous follistatin is commonly upregulated in both nontumorous and tumorous liver tissues of parkin-deficient mice. Parkin deficiency resulted in suppression of caspase activation and rendered hepatocytes resistant to apoptosis in a follistatin-dependent manner. These results suggested that parkin deficiency caused enhanced hepatocyte proliferation and resistance to apoptosis, resulting in hepatic tumor development, partially through the upregulation of endogenous follistatin. The finding that parkin-deficient mice are susceptible to hepatocarcinogenesis provided the first evidence showing that parkin is indeed a tumor suppressor gene.


systematic_name: M1342
exact_source: Table 3S
source_species_code: MM
GEO_id: GSE9651
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes commonly down-regulated in both non-tumorous and tumorous liver tissues of PARK2 [GeneID=5071] knockout mice.

description_full:
  The parkin was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism. Deregulation of the parkin gene, however, has been observed in various human cancers, suggesting that the parkin gene may be important in tumorigenesis. To gain insight into the physiologic role of parkin, we generated parkin-/- mice lacking exon 3 of the parkin gene. We demonstrated here that parkin-/- mice had enhanced hepatocyte proliferation and developed macroscopic hepatic tumors with the characteristics of hepatocellular carcinoma. Microarray analyses revealed that parkin deficiency caused the alteration of gene expression profiles in the liver. Among them, endogenous follistatin is commonly upregulated in both nontumorous and tumorous liver tissues of parkin-deficient mice. Parkin deficiency resulted in suppression of caspase activation and rendered hepatocytes resistant to apoptosis in a follistatin-dependent manner. These results suggested that parkin deficiency caused enhanced hepatocyte proliferation and resistance to apoptosis, resulting in hepatic tumor development, partially through the upregulation of endogenous follistatin. The finding that parkin-deficient mice are susceptible to hepatocarcinogenesis provided the first evidence showing that parkin is indeed a tumor suppressor gene.


systematic_name: M1343
exact_source: Table S1
source_species_code: MM
GEO_id: GSE9651
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in tumorous  liver tissues from PARK2 [GeneID=5071] knockout mice compared to the normal, non-tumorous tissue from wild type mice.

description_full:
[cell repeats an earlier one in this file: 1317 characters]


systematic_name: M1346
exact_source: Table 1S: logFC > 0
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the urogenital sinus (UGS) of day E16 females exposed to the androgen dihydrotestosterone [PubChem=10635] for 6 h.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1349
exact_source: Table 2S: logFC < 0
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the urogenital sinus (UGS) of day E16 females exposed to the androgen dihydrotestosterone [PubChem=10635] for 12 h.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1353
exact_source: Table 13S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (up-regulated at 6 h dihydrotestosterone [PubChem=10635]) which are also up-regulated in normal epithelium vs high grade prostatic intraepithelial neoplasia (PIN).

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1355
exact_source: Table 13S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (down-regulated at 6 h dihydrotestosterone [PubChem=10635]) which are also down-regulated in normal epithelium vs high grade prostatic intraepithelial neoplasia (PIN).

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1356
exact_source: Table 14S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (up-regulated at 6 hr dihydrotestosterone [PubChem=10635]) which are also up-regulated in high grade prostatic intraepithelial neoplasia (PIN) vs invasive cancer.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1357
exact_source: Table 14S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (down-regulated at 6 hr dihydrotestosterone [PubChem=10635]) which are also down-regulated in high grade prostatic intraepithelial neoplasia (PIN) vs invasive cancer.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1358
exact_source: Table 16S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (up-regulated at 6 hr dihydrotestosterone [PubChem=10635]) which are also up-regulated in localized vs metastatic prostate cancers.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1359
exact_source: Table 16S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (down-regulated at 6 hr dihydrotestosterone [PubChem=10635]) which are also down-regulated in localized vs metastatic prostate cancers.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1362
exact_source: Table 17S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (up-regulated at 12 hr dihydrotestosterone [PubChem=10635]) which are also up-regulated in high grade prostatic intraepithelial neoplasia (PIN) vs invasive cancer.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1363
exact_source: Table 17S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (down-regulated at 12 hr dihydrotestosterone [PubChem=10635]) which are also down-regulated in high grade prostatic intraepithelial neoplasia (PIN) vs invasive cancer.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1364
exact_source: Table 18S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (up-regulated at 48 hr dihydrotestosterone [PubChem=10635]) which are also up-regulated in high grade prostatic intraepithelial neoplasia (PIN) vs invasive cancer.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1366
exact_source: Table 18S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (down-regulated at 48 hr dihydrotestosterone [PubChem=10635]) which are also down-regulated in high grade prostatic intraepithelial neoplasia (PIN) vs invasive cancer.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1371
exact_source: Table 15S
source_species_code: MM
GEO_id: GSE12077
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Early prostate development genes (up-regulated at 6 hr dihydrotestosterone [PubChem=10635]) which are also up-regulated in lower grade vs higher grade locally invasive prostate cancers.

description_full:
[cell repeats an earlier one in this file: 2415 characters]


systematic_name: M1377
exact_source: Fig 2e: red in Mut
source_species_code: MM
GEO_id: GSE6078
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the intestine after the tissue specific knockout of PTEN [GeneID=5728] by Cre-lox.

description_full:
  Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector beta-catenin. Akt phosphorylates beta-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of beta-catenin.


systematic_name: M1379
exact_source: Fig 2e: green in Mut
source_species_code: MM
GEO_id: GSE6078
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the intestine after the tissue specific knockout of PTEN [GeneID=5728] by Cre-lox.

description_full:
  Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts, which contain intestinal stem cells (ISCs). In mice, widespread deletion of the tumor suppressor Phosphatase and tensin homolog (PTEN) generates hamartomatous intestinal polyps with epithelial and stromal involvement. Using this model, we have established the relationship between stem cells and polyp and tumor formation. PTEN helps govern the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN-deficient mice, excess ISCs initiate de novo crypt formation and crypt fission, recapitulating crypt production in fetal and neonatal intestine. The PTEN-Akt pathway probably governs stem cell activation by helping control nuclear localization of the Wnt pathway effector beta-catenin. Akt phosphorylates beta-catenin at Ser552, resulting in a nuclear-localized form in ISCs. Our observations show that intestinal polyposis is initiated by PTEN-deficient ISCs that undergo excessive proliferation driven by Akt activation and nuclear localization of beta-catenin.


systematic_name: M17811
exact_source: Table 2S: Z acore < 0
source_species_code: MM
GEO_id: GSE9249
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in post-GC, BCL6 [GeneID=604] dependent B cell non-Hodgkin's lymphoma (B-NHL) vs MYC [GeneID=4609] driven pre-GC lymphoma.

description_full:
  Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.


systematic_name: M2817
exact_source: Table 1S: PFC up
source_species_code: MM
GEO_id: GSE10784
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in prefrontal cortex (PFC) of mice carrying a hemizygotic microdeletion in the 22q11.2 region.

description_full:
  Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. We analyzed an engineered mouse strain carrying a chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. We uncovered a previously unknown alteration in the biogenesis of microRNAs (miRNAs) and identified a subset of brain miRNAs affected by the microdeletion. We provide evidence that the abnormal miRNA biogenesis emerges because of haploinsufficiency of the Dgcr8 gene, which encodes an RNA-binding moiety of the 'microprocessor' complex and contributes to the behavioral and neuronal deficits associated with the 22q11.2 microdeletion.


systematic_name: M12050
exact_source: Table 1S: HPC up
source_species_code: MM
GEO_id: GSE10784
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in hyppocampus of mice carrying a hemizygotic microdeletion in the 22q11.2 region.

description_full:
  Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. We analyzed an engineered mouse strain carrying a chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. We uncovered a previously unknown alteration in the biogenesis of microRNAs (miRNAs) and identified a subset of brain miRNAs affected by the microdeletion. We provide evidence that the abnormal miRNA biogenesis emerges because of haploinsufficiency of the Dgcr8 gene, which encodes an RNA-binding moiety of the 'microprocessor' complex and contributes to the behavioral and neuronal deficits associated with the 22q11.2 microdeletion.


systematic_name: M17954
exact_source: Table 1S: HPC down
source_species_code: MM
GEO_id: GSE10784
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in hyppocampus of mice carrying a hemizygotic microdeletion in the 22q11.2 region.

description_full:
[cell repeats an earlier one in this file: 692 characters]


systematic_name: M6139
exact_source: Table 2S
source_species_code: MM
GEO_id: GSE10784
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes located outside the microdeletion region in 22q11 which were differentially expressed in the same manner both in hyppocampus and prefrontal cortex.

description_full:
[cell repeats an earlier one in this file: 692 characters]


systematic_name: M6455
exact_source: Table 4S: Pre-BI
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the Pre-BI stage.

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M4856
exact_source: Table 4S: Large Pre-BII
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the  Large Pre-BII stage.

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M19751
exact_source: Table 4S: Small Pre-BII
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the Small Pre-BII stage.

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M13396
exact_source: Table 4S: Small Pre-BII
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the Small Pre-BII stage.

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M11262
exact_source: Table 4S: Immature B
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the B lymphocyte developmental signature based on expression profiling of lymphomas from the Emu-myc transgenic mice: the immature B stage.

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M17083
exact_source: Table 4S: Mature B
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the  mature B

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M15847
exact_source: Table 4S: Mature B
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: the  mature B

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M1487
exact_source: Table 4S: Plasma Cell
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: plasma cell.

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M19509
exact_source: Table 4S: Plasma Cell
source_species_code: MM
GEO_id: GSE7897
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the B lymphocyte developmental signature, based on expression profiling of lymphomas from the Emu-myc transgenic mice: plasma cell.

description_full:
[cell repeats an earlier one in this file: 1077 characters]


systematic_name: M7669
exact_source: Fig 1S: UP in medulloblastoma, DOWN in cerebellum
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in medulloblastoma tumors from animals with  inactivating mutations of one copy of PTCH1 or SUFU [GeneID=5727;51684] in conjunction with TP53 [GeneID=7157] loss.

description_full:
  The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.


systematic_name: M16478
exact_source: Fig 1S: DOWN in medulloblastoma, UP in cerebellum
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in medulloblastoma tumors from animals with  inactivating mutations of one copy of PTCH1 or SUFU [GeneID=5727;51684] in conjunction with TP53 [GeneID=7157] loss.

description_full:
  The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.


systematic_name: M1398
exact_source: Table 1S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes implicated in apoptosis that were up-regulated in duodenum of CD44 [GeneID=960] knockout mice.

description_full:
  Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or beta-catenin plays a critical role in the initiation of colorectal cancer. These mutations cause constitutively active beta-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to colorectal cancer precursor lesions, called dysplastic aberrant crypt foci. CD44 is a prominent WNT signaling target in the intestine and is selectively expressed on the renewing epithelial cells lining the crypts. The expression of CD44 is dramatically increased in aberrant crypt foci in both humans and tumor-susceptible Apc(Min/+) mice, suggesting a role for CD44 in intestinal tumorigenesis. To study this role, we crossed C57BL/6J-Cd44(-/-) mice with C57BL/6J-Apc(Min/+) mice. Compared with C57BL/6J-Cd44(+/+)/Apc(Min/+) mice, C57BL/6J-Cd44(-/-)/Apc(Min/+) mice showed an almost 50% reduction in the number of intestinal adenomas. This reduction was primarily caused by a decrease in the formation of aberrant crypts, implying the involvement of CD44 in tumor initiation. The absence of CD44 in the normal (nonneoplastic) crypts of Cd44(-/-)/Apc(Min/+) mice did not alter the proliferative capacity and size of the intestinal stem cell and transit-amplifying compartments. However, compared with Cd44(+/+)/Apc(Min/+) mice, Cd44(-/-)/Apc(Min/+) showed an increase in the number of apoptotic epithelial cells at the base of the crypt which correlated with an increased expression of the proapoptotic genes Bok and Dr6. Our results show an important role for CD44 in intestinal tumorigenesis and suggest that CD44 does not affect proliferation but is involved in the control of the balance between survival and apoptosis in the intestinal crypt.


systematic_name: M1400
exact_source: Table 1S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes implicated in apoptosis that were down-regulated in duodenum of CD44 [GeneID=960] knockout mice.

description_full:
  Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or beta-catenin plays a critical role in the initiation of colorectal cancer. These mutations cause constitutively active beta-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to colorectal cancer precursor lesions, called dysplastic aberrant crypt foci. CD44 is a prominent WNT signaling target in the intestine and is selectively expressed on the renewing epithelial cells lining the crypts. The expression of CD44 is dramatically increased in aberrant crypt foci in both humans and tumor-susceptible Apc(Min/+) mice, suggesting a role for CD44 in intestinal tumorigenesis. To study this role, we crossed C57BL/6J-Cd44(-/-) mice with C57BL/6J-Apc(Min/+) mice. Compared with C57BL/6J-Cd44(+/+)/Apc(Min/+) mice, C57BL/6J-Cd44(-/-)/Apc(Min/+) mice showed an almost 50% reduction in the number of intestinal adenomas. This reduction was primarily caused by a decrease in the formation of aberrant crypts, implying the involvement of CD44 in tumor initiation. The absence of CD44 in the normal (nonneoplastic) crypts of Cd44(-/-)/Apc(Min/+) mice did not alter the proliferative capacity and size of the intestinal stem cell and transit-amplifying compartments. However, compared with Cd44(+/+)/Apc(Min/+) mice, Cd44(-/-)/Apc(Min/+) showed an increase in the number of apoptotic epithelial cells at the base of the crypt which correlated with an increased expression of the proapoptotic genes Bok and Dr6. Our results show an important role for CD44 in intestinal tumorigenesis and suggest that CD44 does not affect proliferation but is involved in the control of the balance between survival and apoptosis in the intestinal crypt.


systematic_name: M1401
exact_source: Tabke 1: indirect correlation
source_species_code: MM
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression in bone marrow samples correlated inversely with increased levels of serum IL5 [GeneID=3567].

description_full:
  Interleukin-5 (IL-5) is a hematopoietic differentiation factor that promotes the development of mature eosinophils from progenitors in bone marrow. We present a multifactorial microarray study documenting the transcriptional events in bone marrow of wild-type and IL-5-deficient mice at baseline and in response to infection with Schistosoma mansoni. The microarray data were analyzed by a 4-way subtractive algorithm that eliminated confounding non-IL-5-related sequelae of schistosome infection as well as alterations in gene expression among uninfected mice. Among the most prominent findings, we observed 7- to 40-fold increased expression of transcripts encoding the classic eosinophil granule proteins (eosinophil peroxidase, major basic protein, the ribonucleases) together with arachidonate-15-lipoxygenase and protease inhibitor plasminogen activator inhibitor 2 (PAI-2), in the IL-5-producing, infected wild-type mice only. This was accompanied by increased transcription of genes involved in secretory protein biosynthesis and granule-vesicle formation. Interestingly, we did not detect increased expression of genes encoding eosinophil-related chemokine receptors (CCR1, CCR3) or members of the GATA or CCAAT/enhancer binding protein (C/EBP) transcription factor families. These data suggest that the IL-5-responsive progenitors in the mouse bone marrow are already significantly committed to the eosinophil lineage and that IL-5 promotes differentiation of these committed progenitors into cells with recognizable and characteristic cytoplasmic granules and granule proteins.


description_brief: Genes up-regulated in MEF cells (embryonic fibroblasts) by overexpression of HOXC8 [GeneID=3224].
systematic_name: M1402
exact_source: Table 2: mRNA that increases in the overexpression of Hoxc8
source_species_code: MM
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_full:
  Hox genes encode transcription factors that control spatial patterning during embryogenesis. To date, downstream targets of Hox genes have proven difficult to identify. Here, we describe studies designed to identify target genes under the control of the murine transcription factor Hoxc8. We used a mouse 16,463 gene oligonucleotide microarray to identify mRNAs whose expression was altered by the overexpression of Hoxc8 in C57BL/6J mouse embryo fibroblasts (MEF) in cell culture (in vitro). We identified a total of 34 genes whose expression was changed by 2-fold or greater: 16 genes were up-regulated, and 18 genes were down-regulated. The majority of genes encoded proteins involved in critical biological processes, such as cell adhesion, migration, metabolism, apoptosis, and tumorigenesis. Two genes showed high levels of regulation: (i) secreted phosphoprotein 1 (Spp1), also known as osteopontin (OPN), was down-regulated 4.8-fold, and (ii) frizzled homolog 2 (Drosophila) (Fzd2) was up-regulated 4.4-fold. Chromatin immunoprecipitation (ChIP) analysis confirmed the direct interaction between the OPN promoter and Hoxc8 protein in vivo, supporting the view that OPN is a direct transcriptional target of Hoxc8.


systematic_name: M10331
exact_source: Table 3: Fgf3
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression is coregulated with that of FGF3 [GeneID=2248] in hematopoietic stem cells (HSC).

description_full:
  We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.


systematic_name: M8699
exact_source: Table 2S
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Transcripts in hematopoietic stem cells (HSC) which are cis-regulated (i.e., modulated by a QTL (quantitative trait locus) in close proximity to the gene).

description_full:
[cell repeats an earlier one in this file: 1095 characters]


systematic_name: M17500
exact_source: Table 2S: CIS REGULATED TRANSCRIPTS
source_species_code: MM
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Best cis-regulated quantitative trait loci (QTLs) in the mouse genome which modulate transcription in brain tissue.

description_full:
  Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred strains, for which we have extensive SNP and haplotype data. We integrated a complementary database comprising 25 years of legacy phenotypic data on these strains. Covariance among gene expression and pharmacological and behavioral traits is often highly significant, corroborates known functional relations and is often generated by common quantitative trait loci. We found that a small number of major-effect quantitative trait loci jointly modulated large sets of transcripts and classical neural phenotypes in patterns specific to each tissue. We developed new analytic and graph theoretical approaches to study shared genetic modulation of networks of traits using gene sets involved in neural synapse function as an example. We built these tools into an open web resource called WebQTL that can be used to test a broad array of hypotheses.


systematic_name: M14242
exact_source: Table 5S
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes trans-regulated by the same QTL (quantitative trait loci) in brain and hematopoietic stem cells (HSC).

description_full:
[cell repeats an earlier one in this file: 1095 characters]


systematic_name: M3592
exact_source: Table 5S
source_species_code: MM
GEO_id: GSE1921
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Up-regulated in CD8+ [GeneID=925] T lymphocytes undergoing homeostatic proliferation (HP) versus the naive cells; these genes are not up-regulated versus effector or memory cell population.

description_full:
  Naive T cells proliferate independently of cognate antigen when introduced into lymphopenic hosts. Lymphopenia-induced proliferation depends on low-affinity MHC/self-peptide complexes and on IL-7. To elucidate the intracellular signals mediating this proliferation, we analyzed changes in gene expression in naive CD8+ T cells at different times after their transfer into a lymphopenic environment. The genes induced in response to lymphopenia were largely an attenuated subset of those turned up by full antigenic stimulation, including genes related to cell cycling, whereas excluding genes specifically associated with effector activity. After the initial phase of proliferation in an empty compartment, the naive T cells adopted a stable pattern of gene expression similar to that of antigen-experienced memory cells. Thus, T cells proliferating in lymphopenic hosts do not exhibit a unique gene-expression profile, instead relying on traditional signals for this antigen-independent proliferation; this process ultimately results in differentiation to authentic memory cells.


systematic_name: M13133
exact_source: Table 4S
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes associated with the same cis-regulatory QTL (quantitative trait loci) in both brain and hematopoietic stem cells (HSC).

description_full:
[cell repeats an earlier one in this file: 1095 characters]


systematic_name: M12486
exact_source: Table 3: Runx1
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression is coregulated with that of RUNX1 [GeneID=861] in hematopoietic stem cells (HSC).

description_full:
[cell repeats an earlier one in this file: 1095 characters]


systematic_name: M7189
exact_source: Table 2S: TRANS REGULATED TRANSCRIPTS
source_species_code: MM
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Best trans-regulated quantitative trait loci (QTLs) in the mouse genome which modulate transcription in brain tissue.

description_full:
[cell repeats an earlier one in this file: 1344 characters]


systematic_name: M427
exact_source: Table 1S
source_species_code: MM
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Neurologically relevant transcripts with highest variance accounted for by mouse strain (genotype) differences.

description_full:
[cell repeats an earlier one in this file: 1344 characters]


systematic_name: M4519
exact_source: Table 1S
source_species_code: MM
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Neurologically relevant transcripts with highest abundance fold range in brain tissue among mouse strains.

description_full:
[cell repeats an earlier one in this file: 1344 characters]


systematic_name: M1415
exact_source: Table 1: Direct correlation
source_species_code: MM
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression in bone marrow samples correlated directly with increased levels of serum IL5 [GeneID=3567].

description_full:
  Interleukin-5 (IL-5) is a hematopoietic differentiation factor that promotes the development of mature eosinophils from progenitors in bone marrow. We present a multifactorial microarray study documenting the transcriptional events in bone marrow of wild-type and IL-5-deficient mice at baseline and in response to infection with Schistosoma mansoni. The microarray data were analyzed by a 4-way subtractive algorithm that eliminated confounding non-IL-5-related sequelae of schistosome infection as well as alterations in gene expression among uninfected mice. Among the most prominent findings, we observed 7- to 40-fold increased expression of transcripts encoding the classic eosinophil granule proteins (eosinophil peroxidase, major basic protein, the ribonucleases) together with arachidonate-15-lipoxygenase and protease inhibitor plasminogen activator inhibitor 2 (PAI-2), in the IL-5-producing, infected wild-type mice only. This was accompanied by increased transcription of genes involved in secretory protein biosynthesis and granule-vesicle formation. Interestingly, we did not detect increased expression of genes encoding eosinophil-related chemokine receptors (CCR1, CCR3) or members of the GATA or CCAAT/enhancer binding protein (C/EBP) transcription factor families. These data suggest that the IL-5-responsive progenitors in the mouse bone marrow are already significantly committed to the eosinophil lineage and that IL-5 promotes differentiation of these committed progenitors into cells with recognizable and characteristic cytoplasmic granules and granule proteins.


systematic_name: M3254
exact_source: Table 3: Fli1
source_species_code: MM
GEO_id: GSE2031
contributor: Jean Junior
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression is coregulated with that of FLI1 [GeneID=2313] in hematopoietic stem cells (HSC).

description_full:
[cell repeats an earlier one in this file: 1095 characters]


systematic_name: M10845
exact_source: Table 4S
source_species_code: MM
GEO_id: GSE1921
contributor: Kate Stafford
contrib_organization: MSigDB Team
description_brief:
  'Memory genes' expressed uniquely in CD8+ [GeneID=925] memory T lymphocytes (compared with effector or naive cells)

description_full:
  Naive T cells proliferate independently of cognate antigen when introduced into lymphopenic hosts. Lymphopenia-induced proliferation depends on low-affinity MHC/self-peptide complexes and on IL-7. To elucidate the intracellular signals mediating this proliferation, we analyzed changes in gene expression in naive CD8+ T cells at different times after their transfer into a lymphopenic environment. The genes induced in response to lymphopenia were largely an attenuated subset of those turned up by full antigenic stimulation, including genes related to cell cycling, whereas excluding genes specifically associated with effector activity. After the initial phase of proliferation in an empty compartment, the naive T cells adopted a stable pattern of gene expression similar to that of antigen-experienced memory cells. Thus, T cells proliferating in lymphopenic hosts do not exhibit a unique gene-expression profile, instead relying on traditional signals for this antigen-independent proliferation; this process ultimately results in differentiation to authentic memory cells.


systematic_name: M10660
exact_source: Table 3
source_species_code: MM
GEO_id: GSE108,GSE109
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the uteri of ovariectomized mice 6 h after progesterone [PubChem=5994] injection: HOXA10 [GeneID=3206] knockout vs wild type animals.

description_full:
[cell repeats an earlier one in this file: 952 characters]


systematic_name: M1433
exact_source: Table 8
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated during myeloid differentiation induced by tretinoin (ATRA) [PubChem=444795] and IL3 [GeneID=3652] in the EML cell line (myeloid progenitor).

description_full:
  With the goal of creating a resource for in-depth study of myelopoiesis, we have executed a 2-pronged strategy to obtain a complementary DNA (cDNA) clone set enriched in hematopoietic genes. One aspect is a library subtraction to enrich for underrepresented transcripts present at early stages of hematopoiesis. For this, a hematopoietic cDNA library from primary murine bone marrow cells enriched for primitive progenitors was used as tester. The subtraction used 10 000 known genes and expressed sequence tags (ESTs) as driver. The 2304 randomly picked clones from the subtracted cDNA libraries represent 1255 distinct genes, of which 622 (50%) are named genes, 386 (30%) match uncharacterized ESTs, and 247 (20%) are novel. The second aspect of our strategy was to complement this subtracted library with genes known to be involved in myeloid cell differentiation and function. The resulting cDNAs were arrayed on polylysine-coated glass slides. The microarrays were used to analyze gene expression in primary and cultured murine bone marrow-derived progenitors. We found expression of various types of genes, including regulatory cytokines and their receptors, signal transduction genes, and transcription factors. To assess gene expression during myeloid differentiation, we examined patterns of change during induced differentiation of EML cells. Several hundred of the genes underwent fluctuations in expression level during myeloid cell differentiation. The complete database, accessible on the World Wide Web at http://yale130132115135.med.yale.edu/, allows for retrieval of information regarding these genes. Our microarray allows for genomewide expression analysis of myeloid stem cells, which will help in defining the regulatory mechanisms of stem cell differentiation.


systematic_name: M1436
exact_source: Table 2
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in day 6 embryoid bodies derived from embryonic stem cells (ES) with HEX [GeneID=3087] knockout.

description_full:
  The first hematopoietic and endothelial progenitors are derived from a common embryonic precursor termed the hemangioblast. The genetic cascades that regulate the differentiation of the hemangioblast to hematopoietic and endothelial cells are largely unknown. In general, much of embryonic development is coordinately regulated by temporal and spatial expression of transcription factors, such as the Homeobox (Hox) gene family. We and others isolated a divergent homeobox gene termed Hex (or Prh) that is preferentially expressed in hematopoietic and endothelial cells. Using in vitro Hex-/- embryonic stem (ES) cell differentiation, in vivo yolk sac hematopoietic progenitor assays, and chimeric mouse analysis, we found that Hex is required for differentiation of the hemangioblast to definitive embryonic hematopoietic progenitors and to a lesser extent endothelial cells. Therefore, Hex is a novel regulator of hemangioblast differentiation to hematopoietic and endothelial cells.


systematic_name: M1437
exact_source: Table 2
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in myeloid progenitors immortalized by HOXA9 [GeneID=3205] vs those immortalized by HOXA9 and MEIS1 [GeneID=4211].

description_full:
  Meis1 is a homeodomain transcription factor coexpressed with Hoxa9 in most human acute myeloid leukemias (AMLs). In mouse models of leukemia produced by Hoxa9, Meis1 accelerates leukemogenesis. Because Hoxa9 immortalizes myeloid progenitors in the absence of Meis1 expression, the contribution of Meis1 toward leukemia remains unclear. Here, we describe a cultured progenitor model in which Meis1 programs leukemogenicity. Progenitors immortalized by Hoxa9 in culture are myeloid-lineage restricted and only infrequently caused leukemia after more than 250 days. Coexpressed Meis1 programmed rapid AML-initiating character, maintained multipotent progenitor potential, and induced expression of genes associated with short-term hematopoietic stem cells (HSCs), such as FLT3 and CD34, whose expression also characterizes the leukemia-initiating stem cells of human AML. Meis1 leukemogenesis functions required binding to Pbx, binding to DNA, and a conserved function of its C-terminal tail. We hypothesize that Meis1 is required for the homing and survival of leukemic progenitors within their hematopoietic niches, functions mediated by HSC-specific genes such as CD34 and Fms-like tyrosine kinase 3 (FLT3), respectively. This is the first example of a transcription factor oncoprotein (Meis1) that establishes expression of a tyrosine kinase oncoprotein (FLT3), and explains their coexpression in human leukemia. This cultured progenitor model will be useful to define the genetic basis of leukemogenesis involving Hoxa9 and Meis1.


systematic_name: M1440
exact_source: Fig 5: Upregulated
source_species_code: MM
GEO_id: E-MEXP-213
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Top 50 genes up-regulated in granulocyte/macrophage progenitors (GMP) upon expression of MLL-CBP fusion [GeneID=4297;1387].

description_full:
  Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.


systematic_name: M1445
exact_source: Table 1
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in day 6 embryoid bodies derived from embryonic stem cells (ES) with HEX [GeneID=3087] knockout.

description_full:
  The first hematopoietic and endothelial progenitors are derived from a common embryonic precursor termed the hemangioblast. The genetic cascades that regulate the differentiation of the hemangioblast to hematopoietic and endothelial cells are largely unknown. In general, much of embryonic development is coordinately regulated by temporal and spatial expression of transcription factors, such as the Homeobox (Hox) gene family. We and others isolated a divergent homeobox gene termed Hex (or Prh) that is preferentially expressed in hematopoietic and endothelial cells. Using in vitro Hex-/- embryonic stem (ES) cell differentiation, in vivo yolk sac hematopoietic progenitor assays, and chimeric mouse analysis, we found that Hex is required for differentiation of the hemangioblast to definitive embryonic hematopoietic progenitors and to a lesser extent endothelial cells. Therefore, Hex is a novel regulator of hemangioblast differentiation to hematopoietic and endothelial cells.


systematic_name: M1450
exact_source: Table 2
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in myeloid progenitors immortalized by HOXA9 [GeneID=3205] vs those immortalized by HOXA9 and MEIS1 [GeneID=4211].

description_full:
  Meis1 is a homeodomain transcription factor coexpressed with Hoxa9 in most human acute myeloid leukemias (AMLs). In mouse models of leukemia produced by Hoxa9, Meis1 accelerates leukemogenesis. Because Hoxa9 immortalizes myeloid progenitors in the absence of Meis1 expression, the contribution of Meis1 toward leukemia remains unclear. Here, we describe a cultured progenitor model in which Meis1 programs leukemogenicity. Progenitors immortalized by Hoxa9 in culture are myeloid-lineage restricted and only infrequently caused leukemia after more than 250 days. Coexpressed Meis1 programmed rapid AML-initiating character, maintained multipotent progenitor potential, and induced expression of genes associated with short-term hematopoietic stem cells (HSCs), such as FLT3 and CD34, whose expression also characterizes the leukemia-initiating stem cells of human AML. Meis1 leukemogenesis functions required binding to Pbx, binding to DNA, and a conserved function of its C-terminal tail. We hypothesize that Meis1 is required for the homing and survival of leukemic progenitors within their hematopoietic niches, functions mediated by HSC-specific genes such as CD34 and Fms-like tyrosine kinase 3 (FLT3), respectively. This is the first example of a transcription factor oncoprotein (Meis1) that establishes expression of a tyrosine kinase oncoprotein (FLT3), and explains their coexpression in human leukemia. This cultured progenitor model will be useful to define the genetic basis of leukemogenesis involving Hoxa9 and Meis1.


systematic_name: M1454
exact_source: Table 1
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Target genes for STAT3 [GeneID=20848] in CSF3 [GeneID=12985] signaling during myeloblast differentiation to neutrophils.

description_full:
  The Janus kinase (Jak)-Stat pathway plays an essential role in cytokine signaling. Granulocyte colony-stimulating factor (G-CSF) promotes granulopoiesis and granulocytic differentiation, and Stat3 is the principle Stat protein activated by G-CSF. Upon treatment with G-CSF, the interleukin-3-dependent cell line 32D clone 3(32Dcl3) differentiates into neutrophils, and 32Dcl3 cells expressing dominant-negative Stat3 (32Dcl3/DNStat3) proliferate in G-CSF without differentiation. Gene expression profile and quantitative PCR analysis of G-CSF-stimulated cell lines revealed that the expression of C/EBPalpha was up-regulated by the activation of Stat3. In addition, activated Stat3 bound to CCAAT/enhancer-binding protein (C/EBP)alpha, leading to the enhancement of the transcription activity of C/EBPalpha. Conditional expression of C/EBPalpha in 32Dcl3/DNStat3 cells after G-CSF stimulation abolishes the G-CSF-dependent cell proliferation and induces granulocytic differentiation. Although granulocyte-specific genes, such as the G-CSF receptor, lysozyme M, and neutrophil gelatinase-associated lipocalin precursor (NGAL) are regulated by Stat3, only NGAL was induced by the restoration of C/EBPalpha after stimulation with G-CSF in 32Dcl3/DNStat3 cells. These results show that one of the major roles of Stat3 in the G-CSF signaling pathway is to augment the function of C/EBPalpha, which is essential for myeloid differentiation. Additionally, cooperation of C/EBPalpha with other Stat3-activated proteins are required for the induction of some G-CSF responsive genes including lysozyme M and the G-CSF receptor.


systematic_name: M1455
exact_source: Fig 5: Downregulated
source_species_code: MM
GEO_id: E-MEXP-213
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Top 50 genes down-regulated in granulocyte/macrophage progenitors (GMP) upon expression of MLL-CBP fusion [GeneID=4297;1387].

description_full:
  Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.


systematic_name: M4435
exact_source: Table 2
source_species_code: MM
GEO_id: GSE108,GSE109
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the uteri of ovariectomized mice 6 h after progesterone [PubChem=5994] injection: HOXA10 [GeneID=3206] knockout vs wild type animals.

description_full:
[cell repeats an earlier one in this file: 952 characters]


systematic_name: M1477
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE2082
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Endoplasmic retuculum (ER) stress response (caused by  tunicamycin [PubChem=5282055]) genes dependent on CHOP [GeneID=13198].

description_full:
  Unfolded and malfolded client proteins impose a stress on the endoplasmic reticulum (ER), which contributes to cell death in pathophysiological conditions. The transcription factor C/EBP homologous protein (CHOP) is activated by ER stress, and CHOP deletion protects against its lethal consequences. We find that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha) in stressed cells. Thus, impaired GADD34 expression reduces client protein load and ER stress in CHOP(-/-) cells exposed to perturbations that impair ER function. CHOP(-/-) and GADD34 mutant cells accumulate less high molecular weight protein complexes in their stressed ER than wild-type cells. Furthermore, mice lacking GADD34-directed eIF2alpha dephosphorylation, like CHOP(-/-) mice, are resistant to renal toxicity of the ER stress-inducing drug tunicamycin. CHOP also activates ERO1alpha, which encodes an ER oxidase. Consequently, the ER of stressed CHOP(-/-) cells is relatively hypo-oxidizing. Pharmacological and genetic manipulations that promote a hypo-oxidizing ER reduce abnormal high molecular weight protein complexes in the stressed ER and protect from the lethal consequences of ER stress. CHOP deletion thus protects cells from ER stress by decreasing ER client protein load and changing redox conditions within the organelle.


description_brief: Granule constituents expressed during mouse promyelocytic cell line differentiation to neutrophils.
systematic_name: M1478
exact_source: Table 4
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  Although the mature neutrophil is one of the better characterized mammalian cell types, the mechanisms of myeloid differentiation are incompletely understood at the molecular level. A mouse promyelocytic cell line (MPRO), derived from murine bone marrow cells and arrested developmentally by a dominant-negative retinoic acid receptor, morphologically differentiates to mature neutrophils in the presence of 10 microM retinoic acid. An extensive catalog was prepared of the gene expression changes that occur during morphologic maturation. To do this, 3'-end differential display, oligonucleotide chip array hybridization, and 2-dimensional protein electrophoresis were used. A large number of genes whose mRNA levels are modulated during differentiation of MPRO cells were identified. The results suggest the involvement of several transcription regulatory factors not previously implicated in this process, but they also emphasize the importance of events other than the production of new transcription factors. Furthermore, gene expression patterns were compared at the level of mRNA and protein, and the correlation between 2 parameters was studied. (Blood. 2001;98:513-524)


systematic_name: M1479
exact_source: Table 7
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated during myeloid differentiation induced by tretinoin (ATRA) [PubChem=444795] and IL3 [GeneID=3652] in the EML cell line (myeloid progenitor).

description_full:
  With the goal of creating a resource for in-depth study of myelopoiesis, we have executed a 2-pronged strategy to obtain a complementary DNA (cDNA) clone set enriched in hematopoietic genes. One aspect is a library subtraction to enrich for underrepresented transcripts present at early stages of hematopoiesis. For this, a hematopoietic cDNA library from primary murine bone marrow cells enriched for primitive progenitors was used as tester. The subtraction used 10 000 known genes and expressed sequence tags (ESTs) as driver. The 2304 randomly picked clones from the subtracted cDNA libraries represent 1255 distinct genes, of which 622 (50%) are named genes, 386 (30%) match uncharacterized ESTs, and 247 (20%) are novel. The second aspect of our strategy was to complement this subtracted library with genes known to be involved in myeloid cell differentiation and function. The resulting cDNAs were arrayed on polylysine-coated glass slides. The microarrays were used to analyze gene expression in primary and cultured murine bone marrow-derived progenitors. We found expression of various types of genes, including regulatory cytokines and their receptors, signal transduction genes, and transcription factors. To assess gene expression during myeloid differentiation, we examined patterns of change during induced differentiation of EML cells. Several hundred of the genes underwent fluctuations in expression level during myeloid cell differentiation. The complete database, accessible on the World Wide Web at http://yale130132115135.med.yale.edu/, allows for retrieval of information regarding these genes. Our microarray allows for genomewide expression analysis of myeloid stem cells, which will help in defining the regulatory mechanisms of stem cell differentiation.


description_brief: Genes up-regulated in pro-B lymphocytes after knockout of CREBBP [GeneID=1387].
systematic_name: M17669
exact_source: Table 1S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_full:
  CREB-binding protein (CBP) and its para-log p300 are transcriptional coactivators that physically or functionally interact with over 320 mammalian and viral proteins, including 36 that are essential for B cells in mice. CBP and p300 are generally considered limiting for transcription, yet their roles in adult cell lineages are largely unknown since homozygous null mutations in either gene or compound heterozygosity cause early embryonic lethality in mice. We tested the hypotheses that CBP and p300 are limiting and that each has unique properties in B cells, by using mice with Cre/LoxP conditional knockout alleles for CBP (CBP(flox)) and p300 (p300(flox)), which carry CD19(Cre) that initiates floxed gene recombination at the pro-B-cell stage. CD19(Cre)-mediated loss of CBP or p300 led to surprisingly modest deficits in B-cell numbers, whereas inactivation of both genes was not tolerated by peripheral B cells. There was a moderate decrease in B-cell receptor (BCR)-responsive gene expression in CBP or p300 homozygous null B cells, suggesting that CBP and p300 are essential for this signaling pathway that is crucial for B-cell homeostasis. These results indicate that individually CBP and p300 are partially limiting beyond the pro-B-cell stage and that other coactivators in B cells cannot replace their combined loss.


systematic_name: M1482
exact_source: Table 2S
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in pancreatic cells from mice with double knockout of E2F1 [GeneID=1869] and E2F2 [GeneID=1870] compared to wild type.

description_full:
  E2F transcription factors are thought to be key regulators of cell growth control. Here we use mutant mouse strains to investigate the function of E2F1 and E2F2 in vivo. E2F1/E2F2 compound-mutant mice develop nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia, a reduction in the number and size of acini and islets, and their replacement by ductal structures and adipose tissue. Mutant pancreatic cells exhibit increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2F1/E2F2 compound-mutant pancreas, suggesting that their expression is repressed by E2F1/E2F2 activities and that the inappropriate cell cycle found in the mutant pancreas is likely the result of the deregulated expression of these genes. Interestingly, the expression of ductal cell and adipocyte differentiation marker genes was also upregulated, whereas expression of pancreatic cell marker genes were downregulated. These results suggest that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.


systematic_name: M1488
exact_source: Table 1
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes changed by expression of activated form of HRas[GeneID=3265] in MEF cells (embryonic fibroblast) with or without p65/c-Rel complex [GeneID=5970;5966].

description_full:
  Extensive data indicate that oncoproteins, such as oncogenic H-Ras, initiate signal transduction cascades that ultimately lead to the activation of specific transcription factors. We and others have previously demonstrated that Ras activates the inherent transcriptional activation function of the transcription factor nuclear factor kappaB (NF-kappaB). Supportive of the importance of NF-kappaB in transformation, Ras-induced cellular transformation can be suppressed by expression of IkappaBalpha, an inhibitor of NF-kappaB, or by dominant-negative forms of the upstream activator IkappaB kinase (IKK). However, conclusive evidence for a requirement for NF-kappaB subunits in oncogenic transformation has not been reported. Furthermore, there is little understanding of the gene targets controlled by NF-kappaB that might support oncogenic conversion. The data presented here demonstrate that, although both p65 and c-Rel enhance the frequency of Ras-induced cellular transformation, these NF-kappaB subunits are not essential for Ras to transform spontaneously immortalized murine fibroblasts. Microarray analysis identified a set of genes induced by Ras that is dependent on NF-kappaB for their expression and that likely play contributory roles in promoting Ras-induced oncogenic transformation.


systematic_name: M1492
exact_source: Table 2
source_species_code: MM
contributor: Kevin Vogelsang
contrib_organization: MSigDB Team
description_brief:
  Genes that are rapidly down-regulated as multipotential cells of the FDCP-mix hematopoiesis model undergo differentiation and loose their self-renewal and proliferation properties.

description_full:
  The molecular mechanisms governing self-renewal, differentiation, and lineage specification remain unknown. Transcriptional profiling is likely to provide insight into these processes but, as yet, has been confined to static molecular profiles of stem and progenitors cells. We now provide a comprehensive, statistically robust, and dynamic analysis of multipotent hemopoietic progenitor cells undergoing self-renewal in response to interleukin-3 (IL-3) and multilineage differentiation in response to lineage-affiliated cytokines. Cells undergoing IL-3-dependent proliferative self-renewal displayed striking complexity, including expression of genes associated with different lineage programs, suggesting a highly responsive compartment poised to rapidly execute intrinsically or extrinsically initiated cell fate decisions. A remarkable general feature of early differentiation was a resolution of complexity through the downregulation of gene expression. Although effector genes characteristic of mature cells were upregulated late, coincident with morphological changes, lineage-specific changes in gene expression were observed prior to this, identifying genes which may provide early harbingers of unilineage commitment. Of particular interest were genes that displayed differential behavior irrespective of the lineage elaborated, many of which were rapidly downregulated within 4 to 8 h after exposure to a differentiation cue. These are likely to include genes important in self-renewal, the maintenance of multipotentiality, or the negative regulation of differentiation per se.


systematic_name: M17173
exact_source: Table 6S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the nucleus accumbens (a major reward center in brain) 8 weeks after induction of deltaFosB, a FOSB [GeneID=2354] splice variant.

description_full:
  DeltaFosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of DeltaFosB and the activator protein-1 (AP-1) antagonist DeltacJun. However, unlike CREB, short-term and prolonged DeltaFosB induction had opposing effects on gene expression. Gene expression induced by short-term DeltaFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged DeltaFosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly DeltaFosB dependent. These findings help define the molecular functions of CREB and DeltaFosB and identify clusters of genes that contribute to cocaine addiction.


systematic_name: M1502
exact_source: Table 3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Up-regulated in murine dorsal skin cells at 6 h after treatment with the phorbol ester carcinogen TPA [PubChem=4792].

description_full:
  Malignant transformation of mouse skin by chemical carcinogens and tumour promoters, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process that leads to squamous cell carcinoma (SCC) formation. In an effort to identify tumour-associated genes, we studied the influence of short-term TPA-treatment on the gene expression profile of murine skin. A comprehensive microarray with some 5,000 murine gene specific cDNA fragments was established and hybridised with pooled RNA derived from control and TPA-treated dorsal skin samples. Of these genes, 54 were up- and 35 were down-regulated upon TPA application. Additionally, we performed suppression subtractive hybridisation (SSH) with respective RNA pools to generate and analyse a cDNA library enriched for TPA-inducible genes. Expression data of selected genes were confirmed by quantitative real-time PCR and Northern blot analysis. Comparison of microarray and SSH data revealed that 26% of up-regulated genes identified by expression profiling matched with those present in the SSH library. Besides numerous known genes, we identified a large set of unknown cDNAs that represent previously unrecognised TPA-regulated genes in murine skin with potential function in tumour promotion. Additionally, some TPA-induced genes, such as Sprr1A, Saa3, JunB, Il4ralpha, Gp38, RalGDS and Slpi exhibit high basal level in advanced stages of skin carcinogenesis, suggesting that at least a subgroup of the identified TPA-regulated genes may contribute to tumour progression and metastasis.


systematic_name: M1508
exact_source: Table 2, 4S: FC >= 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Up-regulated in the cerebral cortex of aged (22 months) BALB/c mice, compared to young (2 months) controls

description_full:
  A better understanding of the molecular effects of aging in the brain may help to reveal important aspects of organismal aging, as well as processes that lead to age-related brain dysfunction. In this study, we have examined differences in gene expression in the hypothalamus and cortex of young and aged mice by using high-density oligonucleotide arrays. A number of key genes involved in neuronal structure and signaling are differentially expressed in both the aged hypothalamus and cortex, including synaptotagmin I, cAMP-dependent protein kinase C beta, apolipoprotein E, protein phosphatase 2A, and prostaglandin D. Misregulation of these proteins may contribute to age-related memory deficits and neurodegenerative diseases. In addition, many proteases that play essential roles in regulating neuropeptide metabolism, amyloid precursor protein processing, and neuronal apoptosis are up-regulated in the aged brain and likely contribute significantly to brain aging. Finally, a subset of these genes whose expression is affected by aging are oppositely affected by exposure of mice to an enriched environment, suggesting that these genes may play important roles in learning and memory.


systematic_name: M1512
exact_source: Table 1: Fold-TNFa >= 1.3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Adipocyte abundant genes up-regulated in 3T3-L1 cells (fibroblasts induced to differentiate to adipocytes) in response to TNF [GeneID=7124].

description_full:
[cell repeats an earlier one in this file: 2017 characters]


systematic_name: M1513
exact_source: Table 3S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Up-regulated in the neocortex of aged (30-month) mice subjected to caloric restriction since young adulthood.

description_full:
[cell repeats an earlier one in this file: 1348 characters]


systematic_name: M1516
exact_source: Table 4
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes discriminating between direct (cisplatin, MMS, mitomycin C [PubChem=2767;4156;5746]) and indirect (paclitaxel, hydroxyurea, etoposide [PubChem=4666;3657;36462]) acting genotoxins at 4 h time point.

description_full:
  During the safety evaluation process of new drugs and chemicals, a battery of genotoxicity tests is conducted starting with in vitro genotoxicity assays. Obtaining positive results in in vitro genotoxicity tests is not uncommon. Follow-up studies to determine the biological relevance of positive genotoxicity results are costly, time consuming, and utilize animals. More efficient methods, especially for identifying a putative mode of action like an indirect mechanism of genotoxicity (where DNA molecules are not the initial primary targets), would greatly improve the risk assessment for genotoxins. To this end, we are participating in an International Life Sciences Institute (ILSI) project involving studies of gene expression changes caused by model genotoxins. The purpose of the work is to evaluate gene expression tools in general, and specifically for discriminating genotoxins that are direct-acting from indirect-acting. Our lab has evaluated gene expression changes as well as micronuclei (MN) in L5178Y TK(+/-) mouse lymphoma cells treated with six compounds. Direct-acting genotoxins (where DNA is the initial primary target) that were evaluated included the DNA crosslinking agents, mitomycin C (MMC) and cisplatin (CIS), and an alkylating agent, methyl methanesulfonate (MMS). Indirect-acting genotoxins included hydroxyurea (HU), a ribonucleotide reductase inhibitor, taxol (TXL), a microtubule inhibitor, and etoposide (ETOP), a DNA topoisomerase II inhibitor. Microarray gene expression analysis was conducted using Affymetrix mouse oligonucleotide arrays on RNA samples derived from cells which were harvested immediately after the 4 h chemical treatment, and 20 h after the 4 h chemical treatment. The evaluation of these experimental results yields evidence of differentially regulated genes at both 4 and 24 h time points that appear to have discriminating power for direct versus indirect genotoxins, and therefore may serve as a fingerprint for classifying chemicals when their mechanism of action is unknown.


systematic_name: M3576
exact_source: Table 2S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in the nucleus accumbens (a major reward center in the brain) 8 weeks after induction of CREB1 [GeneID=1385] expression in a transgenic Tet-Off system.

description_full:
  DeltaFosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of DeltaFosB and the activator protein-1 (AP-1) antagonist DeltacJun. However, unlike CREB, short-term and prolonged DeltaFosB induction had opposing effects on gene expression. Gene expression induced by short-term DeltaFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged DeltaFosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly DeltaFosB dependent. These findings help define the molecular functions of CREB and DeltaFosB and identify clusters of genes that contribute to cocaine addiction.


systematic_name: M1534
exact_source: Table 1: Diff. expression =< -1.5
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in c-JunER cells (mammary gland epithelum) by overexpression of IFRD1 [GeneID=3475] off an adenovirus vector.

description_full:
  The mammalian SIN3 complex consists of histone deacetylases (HDAC1, HDAC2), several known proteins (SAP30, N-CoR) and as yet unidentified proteins. Here we show that the mouse tetradecanoyl phorbol acetate induced sequence 7 (TIS7) protein is a novel transcriptional co-repressor that can associate with the SIN3 complex. We have identified tis7 as a gene that is up-regulated upon loss of polarity in a mouse mammary gland epithelial cell line expressing an estrogen-inducible c-JunER fusion protein. In unpolarized cells, TIS7 protein levels increase and TIS7 translocates into the nucleus. Overexpression of tis7 causes loss of polarity and represses a set of genes, as revealed by cDNA microarray analysis. We have shown that TIS7 protein interacts with several proteins of the SIN3 complex (mSin3B, HDAC1, N-CoR and SAP30) by yeast two-hybrid screening and co-immunoprecipitations. TIS7 co-immunoprecipitated HDAC complex is enzymatically active and represses a GAL4-dependent reporter transcription. The transcriptional repression of endogenous genes by tis7 overexpression is HDAC dependent. Thus, we propose TIS7 as a transcriptional co-repressor affecting the expression of specific genes in a HDAC activity-dependent manner during cell fate decisions, e.g. scattering.


systematic_name: M1535
exact_source: Table 1, 3S: FC < -2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Down-regulated in the hypothalamus of aged (22 months) BALB/c mice, compared to young (2 months) controls

description_full:
  A better understanding of the molecular effects of aging in the brain may help to reveal important aspects of organismal aging, as well as processes that lead to age-related brain dysfunction. In this study, we have examined differences in gene expression in the hypothalamus and cortex of young and aged mice by using high-density oligonucleotide arrays. A number of key genes involved in neuronal structure and signaling are differentially expressed in both the aged hypothalamus and cortex, including synaptotagmin I, cAMP-dependent protein kinase C beta, apolipoprotein E, protein phosphatase 2A, and prostaglandin D. Misregulation of these proteins may contribute to age-related memory deficits and neurodegenerative diseases. In addition, many proteases that play essential roles in regulating neuropeptide metabolism, amyloid precursor protein processing, and neuronal apoptosis are up-regulated in the aged brain and likely contribute significantly to brain aging. Finally, a subset of these genes whose expression is affected by aging are oppositely affected by exposure of mice to an enriched environment, suggesting that these genes may play important roles in learning and memory.


systematic_name: M1539
exact_source: Table 12S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the nucleus accumbens (a major reward center in the brain) after 5 days of cocaine [PubChem=5760] treatment.

description_full:
  DeltaFosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of DeltaFosB and the activator protein-1 (AP-1) antagonist DeltacJun. However, unlike CREB, short-term and prolonged DeltaFosB induction had opposing effects on gene expression. Gene expression induced by short-term DeltaFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged DeltaFosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly DeltaFosB dependent. These findings help define the molecular functions of CREB and DeltaFosB and identify clusters of genes that contribute to cocaine addiction.


systematic_name: M1541
exact_source: Table 1S: Fold Change Due to MyoD =< -2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in NIH 3T3 cells (fibroblasts) 24 h after inducing MyoD [GeneID=4654] differentiation program.

description_full:
  The activation of muscle-specific gene expression requires the coordinated action of muscle regulatory proteins and chromatin-remodeling enzymes. Microarray analysis performed in the presence or absence of a dominant-negative BRG1 ATPase demonstrated that approximately one-third of MyoD-induced genes were highly dependent on SWI/SNF enzymes. To understand the mechanism of activation, we performed chromatin immunoprecipitations analyzing the myogenin promoter. We found that H4 hyperacetylation preceded Brg1 binding in a MyoD-dependent manner but that MyoD binding occurred subsequent to H4 modification and Brg1 interaction. In the absence of functional SWI/SNF enzymes, muscle regulatory proteins did not bind to the myogenin promoter, thereby providing evidence for SWI/SNF-dependent activator binding. We observed that the homeodomain factor Pbx1, which cooperates with MyoD to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a SWI/SNF-independent manner, suggesting a two-step mechanism in which MyoD initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by MyoD and other regulatory proteins.


systematic_name: M1543
exact_source: Table 5
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes discriminating between direct (cisplatin, MMS, mitomycin C [PubChem=2767;4156;5746]) and indirect (paclitaxel, hydroxyurea, etoposide [PubChem=4666;3657;36462]) acting genotoxins at 24 h time point.

description_full:
[cell repeats an earlier one in this file: 2037 characters]


systematic_name: M8645
exact_source: Table 5S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the nucleus accumbens (a major reward center in brain) 2 weeks after induction of deltaFosB, a FOSB [GeneID=2354] splice variant.

description_full:
[cell repeats an earlier one in this file: 1161 characters]


systematic_name: M6937
exact_source: Table 1
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes most strongly down-regulated in kidney glomeruli isolated from TCF21 [GeneID=6943] knockout mice.

description_full:
[cell repeats an earlier one in this file: 1631 characters]


description_brief: Genes whose splicing in neocortex was most affected by knock out of NOVA2 [GeneID=4858].
systematic_name: M1551
exact_source: Table 1
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Alternative RNA splicing greatly increases proteome diversity and may thereby contribute to tissue-specific functions. We carried out genome-wide quantitative analysis of alternative splicing using a custom Affymetrix microarray to assess the role of the neuronal splicing factor Nova in the brain. We used a stringent algorithm to identify 591 exons that were differentially spliced in the brain relative to immune tissues, and 6.6% of these showed major splicing defects in the neocortex of Nova2-/- mice. We tested 49 exons with the largest predicted Nova-dependent splicing changes and validated all 49 by RT-PCR. We analyzed the encoded proteins and found that all those with defined brain functions acted in the synapse (34 of 40, including neurotransmitter receptors, cation channels, adhesion and scaffold proteins) or in axon guidance (8 of 40). Moreover, of the 35 proteins with known interaction partners, 74% (26) interact with each other. Validating a large set of Nova RNA targets has led us to identify a multi-tiered network in which Nova regulates the exon content of RNAs encoding proteins that interact in the synapse.


systematic_name: M6813
exact_source: Excel Table 2S: Expression Cluster=HSC Shared
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'HSC Shared': up-regulated in hematopoietic stem cells (HSC) from adult bone marrow and fetal liver.

description_full:
[cell repeats an earlier one in this file: 626 characters]


systematic_name: M1572
exact_source: Table 3S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Up-regulated in the gastrocnemius muscle of aged (30-month) mice subjected to caloric restriction diet since young adulthood.

description_full:
  The gene expression profile of the aging process was analyzed in skeletal muscle of mice. Use of high-density oligonucleotide arrays representing 6347 genes revealed that aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were either completely or partially prevented by caloric restriction, the only intervention known to retard aging in mammals. Transcriptional patterns of calorie-restricted animals suggest that caloric restriction retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage.


systematic_name: M1576
exact_source: Table 3: Clusters 1-18
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Selected genes down-regulated during differentiation of 3T3-L1 cells (fibroblast) into adipocytes in response to adipogenic hormones.

description_full:
  PPAR gamma is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR gamma, such as thiazolidinediones (TZDs), promote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonucleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adipocytes and differentiating preadipocytes to a TZD PPAR gamma agonist in vitro. The expression of 579 genes was significantly up- or down-regulated by more than 1.5-fold during differentiation and/or by treatment with TZD, and these genes were organized into 32 clusters that demonstrated concerted changes in expression of genes controlling cell growth or lipid metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of beta-catenin as a new PPAR gamma target gene. Both mRNA and protein levels for beta-catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts and were further decreased by treatment of adipocytes with PPAR gamma agonists. Treatment of db/db mice with a PPAR gamma agonist also resulted in reduction of beta-catenin mRNA levels in adipose tissue. These results suggest that beta-catenin plays an important role in the regulation of adipogenesis. Thus, the transcriptional patterns revealed in this study further the understanding of adipogenesis process and the function of PPAR gamma activation.


systematic_name: M1581
exact_source: Table 1: Fold-TNFa-TGZ >=1.3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Adipocyte abundant genes up-regulated in 3T3-L1 cells (fibroblasts induced to differentiate to adipocytes) in response to troglitazone [PubChem=5591] and TNF [GeneID=7124].

description_full:
[cell repeats an earlier one in this file: 2017 characters]


description_brief: Genes down-regulated in Sertoli cells from both 4 and 10 week old ETV5 [GeneID=2119] knockout mice.
systematic_name: M1586
exact_source: Table 4S
source_species_code: MM
GEO_id: GSE2205
contributor: John Newman
contrib_organization: University of Washington
description_full:
  Division of spermatogonial stem cells produces daughter cells that either maintain their stem cell identity or undergo differentiation to form mature sperm. The Sertoli cell, the only somatic cell within seminiferous tubules, provides the stem cell niche through physical support and expression of surface proteins and soluble factors. Here we show that the Ets related molecule (ERM) is expressed exclusively within Sertoli cells in the testis and is required for spermatogonial stem cell self-renewal. Mice with targeted disruption of ERM have a loss of maintenance of spermatogonial stem cell self-renewal without a block in normal spermatogenic differentiation and thus have progressive germ-cell depletion and a Sertoli-cell-only syndrome. Microarray analysis of primary Sertoli cells from ERM-deficient mice showed alterations in secreted factors known to regulate the haematopoietic stem cell niche. These results identify a new function for the Ets family transcription factors in spermatogenesis and provide an example of transcriptional control of a vertebrate stem cell niche.


systematic_name: M14523
exact_source: Excel Table 2S: Expression Cluster=ST-HSC Shared
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'ST-HSC Shared': up-regulated in short term hematopoietic stem cells (ST-HSC) from adult bone marrow and fetal liver.

description_full:
[cell repeats an earlier one in this file: 626 characters]


systematic_name: M1592
exact_source: Table 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in 3T3-L1 cells (adipocyte) by insulin [GeneID=3630] which continued to respond normally to insulin in the insulin resistant cells.

description_full:
  We have employed microarray technology using RNA from normal 3T3-L1 adipocytes and from 3T3-L1 adipocytes made insulin-resistant by treatment with tumor necrosis factor-alpha to identify a new class of insulin-responsive genes. These genes continued to respond normally to insulin even though the adipocytes themselves were metabolically insulin-resistant, i.e. they displayed a significantly decreased rate of insulin-stimulated glucose uptake. Approximately 12,000 genes/expressed sequence tags (ESTs) were screened. Of these, 40 genes/ESTs were identified that became insulin-resistant as expected (e.g. Socs-3, junB, and matrix metalloproteinase-11). However, 61 genes/ESTs continued to respond normally to insulin. Although some of these genes were previously shown to be regulated by insulin (e.g. Glut-1 and beta3-adrenergic receptor), other novel insulin-sensitive genes were also identified (e.g. Egr-1, epiregulin, Fra-1, and ABCA1). Real-time reverse transcription-PCR analysis confirmed the expression patterns of several of the differentially expressed genes. One gene that remained insulin-sensitive in the insulin-resistant adipocytes is the transcription factor Egr-1. Using an antisense strategy, we show that tissue factor and macrophage colony-stimulating factor, two cardiovascular risk factors, are downstream EGR-1 target genes in the adipocyte. Taken together, these data support the hypothesis that some signaling pathways remain insulin-sensitive in metabolically insulin-resistant adipocytes. These pathways may promote abnormal gene expression in hyperinsulinemic states like obesity and type II diabetes and thus may contribute to pathologies associated with these conditions.


systematic_name: M1593
exact_source: Table 1A
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes similarly up-regulated in 3T3-L1 cells (fibroblasts able to differentiate to adipocytes) upon stimulation of INSR or IGFR1 by NTF3 [GeneID=3643;3480;4908].

description_full:
  Insulin and insulin-like growth factor-1 (IGF-1) act through highly homologous receptors that engage similar intracellular signaling pathways, yet these hormones serve largely distinct physiological roles in the control of metabolism and growth, respectively. In an attempt to uncover the molecular mechanisms underlying their divergent functions, we compared insulin receptor (IR) and IGF-1 receptor (IGF-1R) regulation of gene expression by microarray analysis, using 3T3-L1 cells expressing either TrkC/IR or TrkC/IGF-1R chimeric receptors to ensure the highly selective activation of each receptor tyrosine kinase. Following stimulation of the chimeric receptors for 4 h, we detected 11 genes to be differentially regulated, of which 10 were up-regulated to a greater extent by the IGF-1R. These included genes involved in adhesion, transcription, transport, and proliferation. The expression of mRNA encoding heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen, was markedly increased by IGF-1R but not IR activation. This effect was dependent on MAPK, but not phosphatidylinositol 3-kinase, and did not require an autocrine loop through the epidermal growth factor receptor. HB-EGF mitogenic activity was detectable in the medium of 3T3-L1 preadipocytes expressing activated IGF-1R but not IR, indicating that the transcriptional response is accompanied by a parallel increase in mature HB-EGF protein. The differential abilities of the IR and IGF-1R tyrosine kinases to stimulate the synthesis and release of a growth factor may provide, at least in part, an explanation for the greater role of the IGF-1R in the control of cellular proliferation.


description_brief: Up-regulated PDGF targets identified by a gene-trap screen.
systematic_name: M1598
exact_source: Table 1: PDGF = Ind
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_full:
  We developed a versatile, high-throughput genetic screening strategy by coupling gene mutagenesis and expression profiling technologies. Using a retroviral gene-trap vector optimized for efficient mutagenesis and cloning, we randomly disrupted genes in mouse embryonic stem (ES) cells and amplified them to construct a cDNA microarray. With this gene-trap array, we show that transcriptional target genes of platelet-derived growth factor (PDGF) can be efficiently and reliably identified in physiologically relevant cells and are immediately accessible to genetic studies to determine their in vivo roles and relative contributions to PDGF-regulated developmental processes. The same platform can be used to search for genes of specific biological relevance in a broad array of experimental settings, providing a fast track from gene identification to functional validation.


systematic_name: M6920
exact_source: Table 1S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the nucleus accumbens (a major reward center in the brain) 8 weeks after induction of CREB1 [GeneID=1385] expression in a transgenic Tet-Off system.

description_full:
[cell repeats an earlier one in this file: 1161 characters]


systematic_name: M13907
exact_source: Table 1S: IRS-1 KO / WT < 1
source_species_code: MM
GEO_id: GSE2556
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Down-regulated in brown preadipocytes with IRS1 [GeneID=3667] knockout vs wild type controls; the knockouts have severe defects in adipocyte differentiation.

description_full:
  The insulin/IGF-1 (insulin-like growth factor 1) signalling pathway promotes adipocyte differentiation via complex signalling networks. Here, using microarray analysis of brown preadipocytes that are derived from wild-type and insulin receptor substrate (Irs) knockout animals that exhibit progressively impaired differentiation, we define 374 genes/expressed-sequence tags whose expression in preadipocytes correlates with the ultimate ability of the cells to differentiate. Many of these genes, including preadipocyte factor-1 (Pref-1) and multiple members of the Wnt signalling pathway, are related to early adipogenic events. Necdin is also markedly increased in Irs knockout cells that cannot differentiate, and knockdown of necdin restores brown adipogenesis with downregulation of Pref-1 and Wnt10a expression. Insulin receptor substrate proteins regulate a necdin-E2F4 interaction that represses peroxisome-proliferator-activated receptor gamma (PPARgamma) transcription via a cyclic AMP response element binding protein (CREB)-dependent pathway. Together these define a key signalling network that is involved in brown preadipocyte determination.


systematic_name: M1600
exact_source: Table 12
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the nucleus accumbens (a major reward center in the brain) after 4 weeks of cocaine [PubChem=5760] treatment.

description_full:
[cell repeats an earlier one in this file: 1161 characters]


systematic_name: M16005
exact_source: Excel Table 2S: Expression Cluster=Intermediate Progenitors Shered
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes in the expression cluster 'Intermediate Progenitors Shared': up-regulated in hematopoietic intemediate progenitor cells from adult bone marrow and fetal liver.

description_full:
[cell repeats an earlier one in this file: 626 characters]


systematic_name: M1609
exact_source: Table 4S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Down-regulated in the neocortex of aged (30-month) mice subjected to caloric restriction since young adulthood.

description_full:
[cell repeats an earlier one in this file: 1348 characters]


systematic_name: M1619
exact_source: Table 1: 3 h or 6 h > 0
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the brain cortex of mice that were exposed to an enriched learning environment for one day.

description_full:
  An enriched environment is known to promote structural changes in the brain and to enhance learning and memory performance in rodents [Hebb, D. O. (1947) Am. Psychol. 2, 306-307]. To better understand the molecular mechanisms underlying these experience-dependent cognitive changes, we have used high-density oligonucleotide microarrays to analyze gene expression in the brain. Expression of a large number of genes changes in response to enrichment training, many of which can be linked to neuronal structure, synaptic plasticity, and transmission. A number of these genes may play important roles in modulating learning and memory capacity.


systematic_name: M1620
exact_source: Table 5
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in 3T3-L1 cells (adipocyte) by insulin [GeneID=3630] but displayed blunted response to insulin the insulin resistant cells.

description_full:
  We have employed microarray technology using RNA from normal 3T3-L1 adipocytes and from 3T3-L1 adipocytes made insulin-resistant by treatment with tumor necrosis factor-alpha to identify a new class of insulin-responsive genes. These genes continued to respond normally to insulin even though the adipocytes themselves were metabolically insulin-resistant, i.e. they displayed a significantly decreased rate of insulin-stimulated glucose uptake. Approximately 12,000 genes/expressed sequence tags (ESTs) were screened. Of these, 40 genes/ESTs were identified that became insulin-resistant as expected (e.g. Socs-3, junB, and matrix metalloproteinase-11). However, 61 genes/ESTs continued to respond normally to insulin. Although some of these genes were previously shown to be regulated by insulin (e.g. Glut-1 and beta3-adrenergic receptor), other novel insulin-sensitive genes were also identified (e.g. Egr-1, epiregulin, Fra-1, and ABCA1). Real-time reverse transcription-PCR analysis confirmed the expression patterns of several of the differentially expressed genes. One gene that remained insulin-sensitive in the insulin-resistant adipocytes is the transcription factor Egr-1. Using an antisense strategy, we show that tissue factor and macrophage colony-stimulating factor, two cardiovascular risk factors, are downstream EGR-1 target genes in the adipocyte. Taken together, these data support the hypothesis that some signaling pathways remain insulin-sensitive in metabolically insulin-resistant adipocytes. These pathways may promote abnormal gene expression in hyperinsulinemic states like obesity and type II diabetes and thus may contribute to pathologies associated with these conditions.


systematic_name: M10427
exact_source: Table 1S: IRS-1 KO / WT > 1
source_species_code: MM
GEO_id: GSE2556
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Up-regulated in brown preadipocytes with IRS1 [GeneID=3667] knockout vs wild type controls; the knockouts have severe defects in adipocyte differentiation.

description_full:
  The insulin/IGF-1 (insulin-like growth factor 1) signalling pathway promotes adipocyte differentiation via complex signalling networks. Here, using microarray analysis of brown preadipocytes that are derived from wild-type and insulin receptor substrate (Irs) knockout animals that exhibit progressively impaired differentiation, we define 374 genes/expressed-sequence tags whose expression in preadipocytes correlates with the ultimate ability of the cells to differentiate. Many of these genes, including preadipocyte factor-1 (Pref-1) and multiple members of the Wnt signalling pathway, are related to early adipogenic events. Necdin is also markedly increased in Irs knockout cells that cannot differentiate, and knockdown of necdin restores brown adipogenesis with downregulation of Pref-1 and Wnt10a expression. Insulin receptor substrate proteins regulate a necdin-E2F4 interaction that represses peroxisome-proliferator-activated receptor gamma (PPARgamma) transcription via a cyclic AMP response element binding protein (CREB)-dependent pathway. Together these define a key signalling network that is involved in brown preadipocyte determination.


systematic_name: M8364
exact_source: Fig. 2S: Down progression
source_species_code: MM
GEO_id: GSE2556
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes showing decreasing expression in brown preadipocytes with increasing ability of the cells to differentiate.

description_full:
  The insulin/IGF-1 (insulin-like growth factor 1) signalling pathway promotes adipocyte differentiation via complex signalling networks. Here, using microarray analysis of brown preadipocytes that are derived from wild-type and insulin receptor substrate (Irs) knockout animals that exhibit progressively impaired differentiation, we define 374 genes/expressed-sequence tags whose expression in preadipocytes correlates with the ultimate ability of the cells to differentiate. Many of these genes, including preadipocyte factor-1 (Pref-1) and multiple members of the Wnt signalling pathway, are related to early adipogenic events. Necdin is also markedly increased in Irs knockout cells that cannot differentiate, and knockdown of necdin restores brown adipogenesis with downregulation of Pref-1 and Wnt10a expression. Insulin receptor substrate proteins regulate a necdin-E2F4 interaction that represses peroxisome-proliferator-activated receptor gamma (PPARgamma) transcription via a cyclic AMP response element binding protein (CREB)-dependent pathway. Together these define a key signalling network that is involved in brown preadipocyte determination.


systematic_name: M1641
exact_source: Table 2: Cluster 3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Cluster 3: genes maximally expressed at 8 hr time point  during differentiation of 3T3-L1 fibroblasts into adipocytes in response to adipogenic hormones.

description_full:
[cell repeats an earlier one in this file: 1360 characters]


description_brief: Genes up-regulated in anergic mouse T helper cells (A.E7), versus non-anergic stimulated controls
systematic_name: M1644
exact_source: Table 1
source_species_code: MM
GEO_id: GSE2323
contributor: John Newman
contrib_organization: University of Washington
description_full:
  T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. E3 ligases are involved in maintaining the anergic state. However, the specific molecules responsible for the induction of anergy have yet to be elucidated. Using microarray analysis we have identified here early growth response gene 2 (Egr-2) and Egr-3 as key negative regulators of T cell activation. Overexpression of Egr2 and Egr3 was associated with an increase in the E3 ubiquitin ligase Cbl-b and inhibition of T cell activation. Conversely, T cells from Egr3(-/-) mice had lower expression of Cbl-b and were resistant to in vivo peptide-induced tolerance. These data support the idea that Egr-2 and Egr-3 are involved in promoting a T cell receptor-induced negative regulatory genetic program.


systematic_name: M1650
exact_source: Table 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in the mouse model of acute lung injury induced by inhaling nickel sulfate [PubChem=24586].

description_full:
  The role of nitric oxide (NO) in acute lung injury remains controversial. Although inhaled NO increases oxygenation in clinical trials, inhibiting NO-synthase (NOS) can be protective. To examine the latter, nickel-exposed mice were treated with saline or NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). Initial microarray analysis of nickel-induced gene expression of saline-treated mice revealed increased inflammatory mediator, matrix injury-repair, and hypoxia-induced factor-mediated sequences and decreased lung-specific (e.g., surfactant-associated protein B and C) sequences. Compared with saline control, L-NAME-treated mice had enhanced survival with attenuated serum nitrate/nitrite, endothelial NOS activity, and lavage neutrophils and protein. Although initial cytokine (i.e., interferon-gamma, interleukins-1beta and -6, macrophage inflammatory protein-2, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) gene expression was similar between groups, subsequent larger cytokine increases only occurred in saline-treated mice. Similarly, surfactant protein gene expression decreased initially in both groups yet was restored subsequently with L-NAME treatment. Interestingly, the role of inducible NOS (iNOS) in these responses seems minimal. iNOS gene expression was unaltered, iNOS activity and nitrotyrosine residues were undetectable, and an iNOS antagonist, aminoguanidine, failed to increase survival. Rather, systemic L-NAME treatment appears to attenuate pulmonary endothelial NOS activity, subsequent cytokine expression, inflammation, and protein permeability, and thereby restores surfactant gene expression and increases survival.


systematic_name: M1651
exact_source: Table 1: 3h and 6 hr > 0
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes up-regulated in the brain cortex of mice that were exposed to an enriched learning environment for 2 or 14 days.

description_full:
  An enriched environment is known to promote structural changes in the brain and to enhance learning and memory performance in rodents [Hebb, D. O. (1947) Am. Psychol. 2, 306-307]. To better understand the molecular mechanisms underlying these experience-dependent cognitive changes, we have used high-density oligonucleotide microarrays to analyze gene expression in the brain. Expression of a large number of genes changes in response to enrichment training, many of which can be linked to neuronal structure, synaptic plasticity, and transmission. A number of these genes may play important roles in modulating learning and memory capacity.


systematic_name: M1654
exact_source: Table 3
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes down-regulated in 3T3-L1 cells (adipocyte) by insulin [GeneID=3630] which continued to respond normally to insulin in the insulin resistant cells.

description_full:
[cell repeats an earlier one in this file: 1704 characters]


systematic_name: M1657
exact_source: Table 4S
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Down-regulated in the gastrocnemius muscle of aged (30-month) mice subjected to caloric restriction diet since young adulthood.

description_full:
  The gene expression profile of the aging process was analyzed in skeletal muscle of mice. Use of high-density oligonucleotide arrays representing 6347 genes revealed that aging resulted in a differential gene expression pattern indicative of a marked stress response and lower expression of metabolic and biosynthetic genes. Most alterations were either completely or partially prevented by caloric restriction, the only intervention known to retard aging in mammals. Transcriptional patterns of calorie-restricted animals suggest that caloric restriction retards the aging process by causing a metabolic shift toward increased protein turnover and decreased macromolecular damage.


systematic_name: M1659
exact_source: Table 2: Genes with negative interaction
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Down-regulated synergystically by gamma-irradiation and 3-aminobenzamine [PubChem=1645], an inhibitor of PARP1 [GeneID=142].

description_full:
  3-Aminobenzamide (3AB) is an inhibitor of poly (ADP-ribose) polymerase (PARP), an enzyme implicated in the maintenance of genomic integrity, which is activated in response to radiation-induced DNA strand breaks. cDNA macroarray membranes containing 1536 clones were used to characterize the gene expression profiles displayed by mouse BALB/3T3 fibroblasts (A31 cell line) in response to ionizing irradiation alone or in combination with 3AB. A31 cells in exponential growth were pre-treated with 3AB 4mM 1h before gamma-irradiation (4Gy), remaining in culture during 6h until harvesting time. A31 cells treated with 3AB alone presented a down-regulation in genes involved in protein processing and cell cycle control, while an up-regulation of genes involved in apoptosis and related to DNA/RNA synthesis and repair was verified. A31 cells irradiated with 4Gy displayed 41 genes differentially expressed, being detected a down-regulation of genes involved in protein processing and apoptosis, and genes controlling the cell cycle. Concomitantly, another set of genes for protein processing and related to DNA/RNA synthesis and repair were found to be up-regulated. A positive or negative interaction effect between 3AB and radiation was verified for 29 known genes. While the combined treatment induced a synergistic effect on the expression of LCK proto-oncogene and several genes related to protein synthesis/processing, a negative interaction effect was found for the expression of genes related to cytoskeleton and extracellular matrix assembly (SATB1 and Anexin III), cell cycle control (tyrosine kinase), and genes participating in DNA/RNA synthesis and repair (RNA helicase, FLAP endonuclease-1, DNA-3 glycosylase methyladenine, splicing factor SC35 and Soh1). The present data open the possibility to investigate the direct participation of specific genes, or gene products acting in concert in the mechanism underlying the cell response to radiation-induced DNA damage under the influence of PARP inhibitor.


systematic_name: M1660
exact_source: Table 1B
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes similarly down-regulated in 3T3-L1 cells (fibroblasts able to differentiate to adipocytes) upon stimulation of INSR or IGFR1 by NTF3 [GeneID=3643;3480;4908].

description_full:
  Insulin and insulin-like growth factor-1 (IGF-1) act through highly homologous receptors that engage similar intracellular signaling pathways, yet these hormones serve largely distinct physiological roles in the control of metabolism and growth, respectively. In an attempt to uncover the molecular mechanisms underlying their divergent functions, we compared insulin receptor (IR) and IGF-1 receptor (IGF-1R) regulation of gene expression by microarray analysis, using 3T3-L1 cells expressing either TrkC/IR or TrkC/IGF-1R chimeric receptors to ensure the highly selective activation of each receptor tyrosine kinase. Following stimulation of the chimeric receptors for 4 h, we detected 11 genes to be differentially regulated, of which 10 were up-regulated to a greater extent by the IGF-1R. These included genes involved in adhesion, transcription, transport, and proliferation. The expression of mRNA encoding heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen, was markedly increased by IGF-1R but not IR activation. This effect was dependent on MAPK, but not phosphatidylinositol 3-kinase, and did not require an autocrine loop through the epidermal growth factor receptor. HB-EGF mitogenic activity was detectable in the medium of 3T3-L1 preadipocytes expressing activated IGF-1R but not IR, indicating that the transcriptional response is accompanied by a parallel increase in mature HB-EGF protein. The differential abilities of the IR and IGF-1R tyrosine kinases to stimulate the synthesis and release of a growth factor may provide, at least in part, an explanation for the greater role of the IGF-1R in the control of cellular proliferation.


systematic_name: M1665
exact_source: Table 2, 4S: FC <= -2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Down-regulated in the cerebral cortex of aged (22 months) BALB/c mice, compared to young (2 months) controls

description_full:
  A better understanding of the molecular effects of aging in the brain may help to reveal important aspects of organismal aging, as well as processes that lead to age-related brain dysfunction. In this study, we have examined differences in gene expression in the hypothalamus and cortex of young and aged mice by using high-density oligonucleotide arrays. A number of key genes involved in neuronal structure and signaling are differentially expressed in both the aged hypothalamus and cortex, including synaptotagmin I, cAMP-dependent protein kinase C beta, apolipoprotein E, protein phosphatase 2A, and prostaglandin D. Misregulation of these proteins may contribute to age-related memory deficits and neurodegenerative diseases. In addition, many proteases that play essential roles in regulating neuropeptide metabolism, amyloid precursor protein processing, and neuronal apoptosis are up-regulated in the aged brain and likely contribute significantly to brain aging. Finally, a subset of these genes whose expression is affected by aging are oppositely affected by exposure of mice to an enriched environment, suggesting that these genes may play important roles in learning and memory.


systematic_name: M1668
exact_source: Table 1, 3S: FC > 2
source_species_code: MM
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Up-regulated in the hypothalamus of aged (22 months) BALB/c mice, compared to young (2 months) controls

description_full:
[cell repeats an earlier one in this file: 1192 characters]


systematic_name: M75
exact_source: Fig. 2S: Up progression
source_species_code: MM
GEO_id: GSE2556
contributor: John Newman
contrib_organization: University of Washington
description_brief:
  Genes showing increasing expression in brown preadipocytes with decreasing ability of the cells to differentiate.

description_full:
[cell repeats an earlier one in this file: 1155 characters]


systematic_name: M1683
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE10218
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated upon skin specific knockout of FOS [GeneID=2353] by cre-lox in the K5-SOS-F mice (express a constitutively active form of SOS1 [GeneID=6654] in the skin).

description_full:
  Expression and function of the oncogenic transcription factor activator protein (AP-1; mainly composed of Jun and Fos proteins) is required for neoplastic transformation of keratinocytes in vitro and tumor promotion as well as malignant progression in vivo. Here, we describe the identification of 372 differentially expressed genes comparing skin tumor samples of K5-SOS-F transgenic mice (Fos(f/f) SOS(+)) with samples derived from animals with a specific deletion of c-Fos in keratinocytes (Fos(Deltaep) SOS(+)). Fos-dependent transcription of selected genes was confirmed by quantitative real-time PCR analysis using tumor samples and mouse back skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). One of the most differentially expressed genes encodes the small mucin-like glycoprotein Podoplanin (Pdpn), whose expression correlates with malignant progression in mouse tumor model systems and human cancer. We found Pdpn and Fos expression in chemically induced mouse skin tumors, and detailed analysis of the Pdpn gene promoter revealed impaired activity in Fos-deficient mouse embryonic fibroblasts, which could be restored by ectopic Fos expression. Direct Fos protein binding to the Pdpn promoter was shown by chromatin immunoprecipitation and a TPA-induced complex at a TPA-responsive element-like motif in the proximal promoter was identified by electrophoretic mobility shift assays. In summary, we could define a Fos-dependent genetic program in a well-established model of skin tumors. Systematic analysis of these novel target genes will guide us in elucidating the molecular mechanisms of AP-1-regulated pathways that are critically implicated in neoplastic transformation and/or malignant progression.


systematic_name: M1695
exact_source: Table 1
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in small intestine tissue from transgenic mice expressing a mutant form of COL13A1 [GeneID=1305], compared to normal controls.

description_full:
  Epithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1(del) expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII-positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII-dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility.


systematic_name: M1697
exact_source: Table 1
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in small intestine tissue from transgenic mice expressing a mutant form of COL13A1 [GeneID=1305], compared to normal controls.

description_full:
  Epithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1(del) expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII-positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII-dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility.


description_brief: Genes up-regulated in NIH3T3 cells (fibroblast) engineered to stably express MUC4 [GeneID=4585].
systematic_name: M1699
exact_source: Table 1
source_species_code: MM
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Numerous studies have established the association of MUC4 with the progression of cancer and metastasis. An aberrant expression of MUC4 is reported in precancerous lesions, indicating its early involvement in the disease process; however, its precise role in cellular transformation has not been explored. MUC4 contains many unique domains and is proposed to affect cell signaling pathways and behavior of the tumor cells. In the present study, to decipher the oncogenic potential of MUC4, we stably expressed the MUC4 mucin in NIH3T3 mouse fibroblast cells. Stable ectopic expression of MUC4 resulted in increased growth, colony formation, and motility of NIH3T3 cells in vitro and tumor formation in nude mice when cells were injected s.c. Microarray analysis showed increased expression of several growth-associated and mitochondrial energy production-associated genes in MUC4-expressing NIH3T3 cells. In addition, expression of MUC4 in NIH3T3 cells resulted in enhanced levels of oncoprotein ErbB2 and its phosphorylated form (pY(1248)-ErbB2). In conclusion, our studies provide the first evidence that MUC4 alone induces cellular transformation and indicates a novel role of MUC4 in cancer biology.


systematic_name: M1701
exact_source: Supplementary Data 3: Table 3
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mammary glands from the CITED1 [GeneID=4435] knockout mice: homozygotic vs. heterozygotic animals.

description_full:
  Expression microarray analysis identified CITED1 among a group of genes specifically upregulated in the pubertal mouse mammary gland. At puberty, CITED1 localizes to the luminal epithelial cell population of the mammary ducts and the body cells of the terminal end buds. Generation of CITED1 gene knockout mice showed that homozygous null mutants exhibit retarded mammary ductal growth at puberty and, in addition, dilated ductal structures with a lack of spatial restriction of the subtending branches. Analysis of CITED1 homozygous null and heterozygous null mammary gland gene expression using microarrays suggested that the mammary-specific phenotype seen in the homozygous null females is due to a disturbance in the transcription of a number of key mediators of pubertal ductal morphogenesis. These include estrogen and TGFbeta responsive genes, such as the EGFR/ErbB2 ligand, amphiregulin, whose transcription we suggest is directly or indirectly regulated by CITED1.


systematic_name: M1703
exact_source: Supplementary Data 3: Table 1
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mammary glands from the CITED1 [GeneID=4435] knockout mice: homozygotic vs. heterozygotic animals.

description_full:
  Expression microarray analysis identified CITED1 among a group of genes specifically upregulated in the pubertal mouse mammary gland. At puberty, CITED1 localizes to the luminal epithelial cell population of the mammary ducts and the body cells of the terminal end buds. Generation of CITED1 gene knockout mice showed that homozygous null mutants exhibit retarded mammary ductal growth at puberty and, in addition, dilated ductal structures with a lack of spatial restriction of the subtending branches. Analysis of CITED1 homozygous null and heterozygous null mammary gland gene expression using microarrays suggested that the mammary-specific phenotype seen in the homozygous null females is due to a disturbance in the transcription of a number of key mediators of pubertal ductal morphogenesis. These include estrogen and TGFbeta responsive genes, such as the EGFR/ErbB2 ligand, amphiregulin, whose transcription we suggest is directly or indirectly regulated by CITED1.


systematic_name: M1704
exact_source: Supplementary Data 3: Table 4
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mammary glands from the CITED1 [GeneID=4435] knockout mice: homozygotic vs wild type (WT) animals.

description_full:
[cell repeats an earlier one in this file: 974 characters]


systematic_name: M1708
exact_source: Supplementary Data 3: Table 2
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mammary glands from the CITED1 [GeneID=4435] knockout mice: homozygotic vs wild type (WT) animals.

description_full:
[cell repeats an earlier one in this file: 974 characters]


systematic_name: M1712
exact_source: Table 1S: neuron-enriched
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes enriched in neurons in the adult mouse brain identified through correlation-based searches seeded with neuron cell-type specific gene expression patterns.

description_full:
  Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.


systematic_name: M1713
exact_source: Table 1S: astrocyte-enriched
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes enriched in astrocytes in the adult mouse brain identified through correlation-based searches seeded with the astrocyte cell-type specific gene expression patterns.

description_full:
  Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.


systematic_name: M1714
exact_source: Table 1S: Oligodendrocyte-enriched
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes enriched in oligodendrocytes in the adult mouse brain identified through correlation-based searches seeded with the oligodendrocyte cell-type specific gene expression patterns.

description_full:
[cell repeats an earlier one in this file: 1123 characters]


systematic_name: M1722
exact_source: Table 3S: MY
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Top 100 ranked genes most specific to  medulla (myelencephalon) hindbrain region of adult mouse brain.

description_full:
[cell repeats an earlier one in this file: 1123 characters]


systematic_name: M1725
exact_source: Table 4S: Distal and Proximal Dendrites
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Transcripts showing subcellular localization to both distal and proximal dendrites in the adult mouse brain.

description_full:
[cell repeats an earlier one in this file: 1123 characters]


systematic_name: M1731
exact_source: Fig 5S: cluster T7
source_species_code: MM
GEO_id: GSE7280,GSE7770,GSE7773
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster T7 of genes with similar expression profiles in thymic T lymphocytes after FOXP3 [GeneID=50943] loss of function (LOF).

description_full:
[cell repeats an earlier one in this file: 1399 characters]


systematic_name: M1732
exact_source: Fig 5S: cluster P2
source_species_code: MM
GEO_id: GSE7280,GSE7773,GSE7770
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster P2 of genes with similar expression profiles in peripheral T ymphocytes after FOXP3 [GeneID=50943] loss of function (LOF).

description_full:
[cell repeats an earlier one in this file: 1399 characters]


systematic_name: M1733
exact_source: Fig 5S: cluster P3
source_species_code: MM
GEO_id: GSE7280,GSE7770,GSE7773
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster P3 of genes with similar expression profiles in peripheral T lymphocytes after FOXP3 [GeneID=50943] loss of function (LOF).

description_full:
[cell repeats an earlier one in this file: 1399 characters]


systematic_name: M1740
exact_source: Supplementary Fig 7D
source_species_code: MM
GEO_id: GSE7773,GSE7280,GSE7770
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  FOXP3 [GeneID=50943] target genes down-regulated in T lymphocytes after stimulation with IL2 [GeneID=3558].

description_full:
[cell repeats an earlier one in this file: 1399 characters]


systematic_name: M3146
exact_source: Table 7aS: fox3p+/fox3p- > 1 & Foxp3 bound (FDR <.10)
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943], dependent on it, and up-regulated in hybridoma cells stimulated by PMA [PubChem=4792] and ionomycin [PubChem=3733].

description_full:
[cell repeats an earlier one in this file: 1390 characters]


systematic_name: M18702
exact_source: Table 7aS: fox3p+/fox3p- <1 & Foxp3 bound (FDR<.10)
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943], dependent on it, and down-regulated in hybridoma cells stimulated by PMA [PubChem=4792] and ionomycin [PubChem=3733].

description_full:
[cell repeats an earlier one in this file: 1390 characters]


systematic_name: M1745
exact_source: Fig 4a
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Direct FOXP3 [GeneID=50943] targets that exhibit consistent transcriptional behavior in hybridoma and in ex vivo T lymphocytes.

description_full:
[cell repeats an earlier one in this file: 1390 characters]


systematic_name: M1747
exact_source: Table 3S: thymus only
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943] and which are down-regulated only in developing (located in the thymus) regulatory CD4+ [GeneID=920] T lymphocytes.

description_full:
[cell repeats an earlier one in this file: 1298 characters]


systematic_name: M1748
exact_source: Table 3S: periphery only
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943] and which are up-regulated only in mature (peripheral blood) regulatory CD4+ [GeneID=920] T lymphocytes.

description_full:
[cell repeats an earlier one in this file: 1298 characters]


systematic_name: M1751
exact_source: Table 3S: periphery only
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943] and which are down-regulated only in mature (peripheral blood) regulatory CD4+ [GeneID=920] T lymphocytes.

description_full:
[cell repeats an earlier one in this file: 1298 characters]


systematic_name: M1754
exact_source: Table 3S: thymus and periphery
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes with promoters bound by FOXP3 [GeneID=50943] and which are down-regulated both in developing (located in the thymus) and mature (from peripheral blood) regulatory CD4+ [GeneID=920] T lymphocytes.

description_full:
[cell repeats an earlier one in this file: 1298 characters]


description_brief: Genes up-regulated after Cre-lox knockout of APC [GeneID=324] in the small intestine.
systematic_name: M1755
exact_source: Table 1AS, 3AS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers, and its loss results in constitutive activity of the beta-catenin-Tcf4 transcription complex. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro, in normal crypts in vivo and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear beta-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.


systematic_name: M1756
exact_source: Table 1BS, 3BS
source_species_code: MM
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated after double Cre-lox knockout  of both APC and MYC [GeneID=324;4609] in small intestine.

description_full:
  The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers, and its loss results in constitutive activity of the beta-catenin-Tcf4 transcription complex. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro, in normal crypts in vivo and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear beta-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.


systematic_name: M1757
exact_source: Table 2S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated after Cre-lox knockout of APC [GeneID=324] in the small intestine that require functional MYC [GeneID=4609].

description_full:
  The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers, and its loss results in constitutive activity of the beta-catenin-Tcf4 transcription complex. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro, in normal crypts in vivo and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear beta-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Apc loss.


systematic_name: M1758
exact_source: Table 4S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Wnt target genes up-regulated after Cre-lox knockout of APC [GeneID=324] in the small intestine that require functional MYC [GeneID=4609].

description_full:
[cell repeats an earlier one in this file: 1299 characters]


description_brief: Genes up-regulated after Cre-lox knockout of LSD1 [GeneID=23028] in pituitary.
systematic_name: M1759
exact_source: Fig 4AS
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Precise control of transcriptional programmes underlying metazoan development is modulated by enzymatically active co-regulatory complexes, coupled with epigenetic strategies. One thing that remains unclear is how specific members of histone modification enzyme families, such as histone methyltransferases and demethylases, are used in vivo to simultaneously orchestrate distinct developmental gene activation and repression programmes. Here, we report that the histone lysine demethylase, LSD1--a component of the CoREST-CtBP co-repressor complex--is required for late cell-lineage determination and differentiation during pituitary organogenesis. LSD1 seems to act primarily on target gene activation programmes, as well as in gene repression programmes, on the basis of recruitment of distinct LSD1-containing co-activator or co-repressor complexes. LSD1-dependent gene repression programmes can be extended late in development with the induced expression of ZEB1, a Krüppel-like repressor that can act as a molecular beacon for recruitment of the LSD1-containing CoREST-CtBP co-repressor complex, causing repression of an additional cohort of genes, such as Gh, which previously required LSD1 for activation. These findings suggest that temporal patterns of expression of specific components of LSD1 complexes modulate gene regulatory programmes in many mammalian organs.


systematic_name: M1764
exact_source: Table 1S: mES d4 +SB431542 & JAK Inh.
source_species_code: MM
GEO_id: GSE7902
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mES cells (mouse embryonic stem cells) after tratment with the ALK [GeneID=238] inhibitor SB-431542 and JAK inhibitor I [PubChem=4521392;5494425].

description_full:
[cell repeats an earlier one in this file: 1234 characters]


systematic_name: M1766
exact_source: Table 1S: mES d3 +JAK Inh.
source_species_code: MM
GEO_id: GSE7902
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mES cells (mouse embryonic stem cells) after tratment with JAK inhibitor I [PubChem=5494425].

description_full:
[cell repeats an earlier one in this file: 1234 characters]


systematic_name: M1769
exact_source: Fig 5S: Cluster A
source_species_code: MM
GEO_id: GSE6135
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster A: genes up-regulated in primary lung tumors driven by KRAS [GeneID=3845] activation and loss of STK11 [GeneID=6794]; also up-regulated in human squamous cell carcinoma (SCC) vs adenocarcinoma subtype of NSCLC (non-small cell lung cancer).

description_full:
  Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.


systematic_name: M1770
exact_source: Table 1
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes required for epigenetic silencing of FAS [GeneID=355] by activated KRAS [GeneID=3845] in NIH 3T3 cells, based on RNAi screen.

description_full:
  The conversion of a normal cell to a cancer cell occurs in several steps and typically involves the activation of oncogenes and the inactivation of tumour suppressor and pro-apoptotic genes. In many instances, inactivation of genes critical for cancer development occurs by epigenetic silencing, often involving hypermethylation of CpG-rich promoter regions. It remains to be determined whether silencing occurs by random acquisition of epigenetic marks that confer a selective growth advantage or through a specific pathway initiated by an oncogene. Here we perform a genome-wide RNA interference (RNAi) screen in K-ras-transformed NIH 3T3 cells and identify 28 genes required for Ras-mediated epigenetic silencing of the pro-apoptotic Fas gene. At least nine of these RESEs (Ras epigenetic silencing effectors), including the DNA methyltransferase DNMT1, are directly associated with specific regions of the Fas promoter in K-ras-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs results in failure to recruit DNMT1 to the Fas promoter, loss of Fas promoter hypermethylation, and derepression of Fas expression. Analysis of five other epigenetically repressed genes indicates that Ras directs the silencing of multiple unrelated genes through a largely common pathway. Last, we show that nine RESEs are required for anchorage-independent growth and tumorigenicity of K-ras-transformed NIH 3T3 cells; these nine genes have not previously been implicated in transformation by Ras. Our results show that Ras-mediated epigenetic silencing occurs through a specific, complex, pathway involving components that are required for maintenance of a fully transformed phenotype.


systematic_name: M1773
exact_source: Fig 4S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in neural progenitor cells (NPC) isolated from E13 cortical tissue of SMRT [GeneID=9612] knockout mice.

description_full:
  A series of transcription factors critical for maintenance of the neural stem cell state have been identified, but the role of functionally important corepressors in maintenance of the neural stem cell state and early neurogenesis remains unclear. Previous studies have characterized the expression of both SMRT (also known as NCoR2, nuclear receptor co-repressor 2) and NCoR in a variety of developmental systems; however, the specific role of the SMRT corepressor in neurogenesis is still to be determined. Here we report a critical role for SMRT in forebrain development and in maintenance of the neural stem cell state. Analysis of a series of markers in SMRT-gene-deleted mice revealed the functional requirement of SMRT in the actions of both retinoic-acid-dependent and Notch-dependent forebrain development. In isolated cortical progenitor cells, SMRT was critical for preventing retinoic-acid-receptor-dependent induction of differentiation along a neuronal pathway in the absence of any ligand. Our data reveal that SMRT represses expression of the jumonji-domain containing gene JMJD3, a direct retinoic-acid-receptor target that functions as a histone H3 trimethyl K27 demethylase and which is capable of activating specific components of the neurogenic program.


systematic_name: M4925
exact_source: Table 1S: AGE
source_species_code: MM
GEO_id: GSE7269
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes classifying non-tumor lung tissues by age after incution of lung cancer by urethane injection [PubChem=5641]: early (24-26 weeks) vs late (46 weeks).

description_full:
  One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a Field Effect around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells >94% of the time. Finally, the protein levels for several Field Effect genes were higher in cell-free BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid.


systematic_name: M13671
exact_source: Table 1S: fold change > 2
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes distinguishing between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage subtypes.

description_full:
  In addition to the directly mutagenic effects of energy deposition in DNA, ionizing radiation is associated with a variety of untargeted and delayed effects that result in ongoing bone marrow damage. Delayed effects are genotype dependent with CBA/Ca mice, but not C57BL/6 mice, susceptible to the induction of damage and also radiation-induced acute myeloid leukemia. Because macrophages are a potential source of ongoing damaging signals, we have determined their gene expression profiles and we show that bone marrow-derived macrophages show widely different intrinsic expression patterns. The profiles classify macrophages derived from CBA/Ca mice as M1-like (pro-inflammatory) and those from C57BL/6 mice as M2-like (anti-inflammatory); measurements of NOS2 and arginase activity in normal bone marrow macrophages confirm these findings. After irradiation in vivo, but not in vitro, C57BL/6 macrophages show a reduction in NOS2 and an increase in arginase activities, indicating a further M2 response, whereas CBA/Ca macrophages retain an M1 phenotype. Activation of specific signal transducer and activator of transcription signaling pathways in irradiated hemopoietic tissues supports these observations. The data indicate that macrophage activation is not a direct effect of radiation but a tissue response, secondary to the initial radiation exposure, and have important implications for understanding genotype-dependent responses and the mechanisms of the hemotoxic and leukemogenic consequences of radiation exposure.


systematic_name: M14515
exact_source: Table 1S: fold change < -2
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes distinguishing between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophage subtypes.

description_full:
  In addition to the directly mutagenic effects of energy deposition in DNA, ionizing radiation is associated with a variety of untargeted and delayed effects that result in ongoing bone marrow damage. Delayed effects are genotype dependent with CBA/Ca mice, but not C57BL/6 mice, susceptible to the induction of damage and also radiation-induced acute myeloid leukemia. Because macrophages are a potential source of ongoing damaging signals, we have determined their gene expression profiles and we show that bone marrow-derived macrophages show widely different intrinsic expression patterns. The profiles classify macrophages derived from CBA/Ca mice as M1-like (pro-inflammatory) and those from C57BL/6 mice as M2-like (anti-inflammatory); measurements of NOS2 and arginase activity in normal bone marrow macrophages confirm these findings. After irradiation in vivo, but not in vitro, C57BL/6 macrophages show a reduction in NOS2 and an increase in arginase activities, indicating a further M2 response, whereas CBA/Ca macrophages retain an M1 phenotype. Activation of specific signal transducer and activator of transcription signaling pathways in irradiated hemopoietic tissues supports these observations. The data indicate that macrophage activation is not a direct effect of radiation but a tissue response, secondary to the initial radiation exposure, and have important implications for understanding genotype-dependent responses and the mechanisms of the hemotoxic and leukemogenic consequences of radiation exposure.


systematic_name: M2776
exact_source: Table 3S: cluster 1
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster 1: genes up-regulated in lung tissue samples from mice with oncogenic form of KRAS [GeneID=3845] and inactivated PTEN [GeneID=5728].

description_full:
  Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non-small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis.


systematic_name: M9118
exact_source: Table 3S: cluster 3
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster 3: genes up-regulated in lung tissue samples from mice with tumor-bearing genotypes (activated KRAS [GeneID=3845] alone or together with inactivated PTEN [GeneID=5728]).

description_full:
  Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non-small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis.


systematic_name: M9362
exact_source: Table 3S: cluster 4
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Cluster 4: genes down-regulated in lung tissue samples from mice with tumor-bearing genotypes (activated KRAS [GeneID=3845] alone or together with inactivated PTEN [GeneID=5728]).

description_full:
[cell repeats an earlier one in this file: 984 characters]


systematic_name: M14636
exact_source: Table 1: Fold change < 0
source_species_code: MM
GEO_id: GSE11836
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated during prostate cancer progression in mice heterozygotic for both NKX3.1 and PTEN [GeneID=4824;5728].

description_full:
  To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors--the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer.


systematic_name: M9874
exact_source: Table 2S
source_species_code: MM
GEO_id: GSE11836
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Mouse orthologs of human prostate cancer tumor markers which were deregulated in mice heterozygotic for both NKX3.1 and PTEN [GeneID=4824;5728].

description_full:
  To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors--the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer.


systematic_name: M1791
exact_source: Table 1: fold expression change < 0
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Epithelial and mesenchymal markers down-regulated in MEF cells (embryonic fibroblasts) after knockout of PRKAR1A [GeneID=5573].

description_full:
  Dysregulation of protein kinase A (PKA) activity, caused by loss of function mutations in PRKAR1A, is known to induce tumor formation in the inherited tumor syndrome Carney complex (CNC) and is also associated with sporadic tumors of the thyroid and adrenal. We have previously shown that Prkar1a(+/-) mice develop schwannomas reminiscent of those seen in CNC and that similar tumors are observed in tissue-specific knockouts (KO) of Prkar1a targeted to the neural crest. Within these tumors, we have previously described the presence of epithelial islands, although the nature of these structures was unclear. In this article, we report that these epithelial structures are derived from KO cells originating in the neural crest. Analysis of the mesenchymal marker vimentin revealed that this protein was markedly down-regulated not only from the epithelial islands, but also from the tumor as a whole, consistent with mesenchymal-to-epithelial transition (MET). In vitro, Prkar1a null primary mouse embryonic fibroblasts, which display constitutive PKA signaling, also showed evidence for MET, with a loss of vimentin and up-regulation of the epithelial marker E-cadherin. Reduction of vimentin protein occurred at the posttranslational level and was rescued by proteasomal inhibition. Finally, this down-regulation of vimentin was recapitulated in the adrenal nodules of CNC patients, confirming an unexpected and previously unrecognized role for PKA in MET.


systematic_name: M6489
exact_source: Table 5S: fold < 0.5
source_species_code: MM
GEO_id: GSE8863
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in cancer stem cells isolated from mammary tumors compared to the non-tumorigenic cells.

description_full:
  Using a syngeneic p53-null mouse mammary gland tumor model that closely mimics human breast cancer, we have identified, by limiting dilution transplantation and in vitro mammosphere assay, a Lin(-)CD29(H)CD24(H) subpopulation of tumor-initiating cells. Upon subsequent transplantation, this subpopulation generated heterogeneous tumors that displayed properties similar to the primary tumor. Analysis of biomarkers suggests the Lin(-)CD29(H)CD24(H) subpopulation may have arisen from a bipotent mammary progenitor. Differentially expressed genes in the Lin(-)CD29(H)CD24(H) mouse mammary gland tumor-initiating cell population include those involved in DNA damage response and repair, as well as genes involved in epigenetic regulation previously shown to be critical for stem cell self-renewal. These studies provide in vitro and in vivo data that support the cancer stem cell (CSC) hypothesis. Furthermore, this p53-null mouse mammary tumor model may allow us to identify new CSC markers and to test the functional importance of these markers.


systematic_name: M1797
exact_source: Table 2S
source_species_code: MM
GEO_id: GSE12694
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  The glioblastoma multiforme (GBM) plasticity signature: genes down-regulated in neural stem cells (NSC) with double knockout of TP53 and PTEN [GeneID=7157;5728] vs those with knockout of TP53 alone.

description_full:
  Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.


description_brief: Genes up-regulated in ex-vivo colonic tissue after treatment with IL22 [GeneID=50616].
systematic_name: M1800
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE10010
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_full:
  Infections by attaching and effacing (A/E) bacterial pathogens, such as Escherichia coli O157:H7, pose a serious threat to public health. Using a mouse A/E pathogen, Citrobacter rodentium, we show that interleukin-22 (IL-22) has a crucial role in the early phase of host defense against C. rodentium. Infection of IL-22 knockout mice results in increased intestinal epithelial damage, systemic bacterial burden and mortality. We also find that IL-23 is required for the early induction of IL-22 during C. rodentium infection, and adaptive immunity is not essential for the protective role of IL-22 in this model. Instead, IL-22 is required for the direct induction of the Reg family of antimicrobial proteins, including RegIIIbeta and RegIIIgamma, in colonic epithelial cells. Exogenous mouse or human RegIIIgamma substantially improves survival of IL-22 knockout mice after C. rodentium infection. Together, our data identify a new innate immune function for IL-22 in regulating early defense mechanisms against A/E bacterial pathogens.


systematic_name: M1828
exact_source: Fig. 5: Sertoli, peritubular, Leydig and/or interstitial cells
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes important for Sertoli, peritubular, Leydig and interstitial cells, based on mouse models with male reproductive defects.

description_full:
[cell repeats an earlier one in this file: 1515 characters]


systematic_name: M1847
exact_source: Fig. 1D
source_species_code: MM
GEO_id: GSE2774
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in highly immune-resistant cancer cell line developed from a susceptible cancer using an in vivo selection strategy.

description_full:
  Immune escape is an important reason why the immune system cannot control tumor growth, but how escape variants emerge during immunotherapy remains poorly understood. Here, we identify a new mechanism of tumor immune escape using an in vivo selection strategy. We generated a highly immune-resistant cancer cell line (P3) by subjecting a susceptible cancer cell line (P0/TC-1) to multiple rounds of in vivo immune selection. Microarray analysis of P0 and P3 revealed that vascular cell adhesion molecule-1 (VCAM-1) is up-regulated in the P3-resistant variant. Retroviral transfer of VCAM-1 into P0 significantly increased its resistance against a vaccine-induced immune response. Analysis of tumors showed a dramatic decrease in the number of tumor-infiltrating cluster of differentiation 8(+) (CD8(+)) T cells in the tumors expressing VCAM-1. In vitro transwell migration assays showed that VCAM-1 can promote the migration of CD8(+) T cells through its interaction with the alpha(4)beta(1) integrin. Site-directed mutagenesis of VCAM-1 at amino acid residues required for interaction with alpha(4)beta(1) integrin completely abolished the immune resistance conferred by VCAM-1 in vivo. Surface staining showed that most renal cell carcinomas (RCC) express VCAM-1, whereas an RCC that responded to vaccination was VCAM-1 negative. These data provide evidence that tumor expression of VCAM-1 represents a new mechanism of immune evasion and has important implications for the development of immunotherapy for human RCC.


systematic_name: M12482
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE12707,GSE13512
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in Paneth cell (part of intestiinal epithelium) of mice with hypomorphic (reduced function) form of ATG16L1 [GeneID=55054].

description_full:
  Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.


systematic_name: M15542
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE9024
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in pre B lymphocyte after induction of physiological DNA double-strand breaks (DSB) by RAG2 [GeneID=5897]; the changes are independent of ATM [GeneID=472] signaling.

description_full:
  DNA double-strand breaks are generated by genotoxic agents and by cellular endonucleases as intermediates of several important physiological processes. The cellular response to genotoxic DNA breaks includes the activation of transcriptional programs known primarily to regulate cell-cycle checkpoints and cell survival. DNA double-strand breaks are generated in all developing lymphocytes during the assembly of antigen receptor genes, a process that is essential for normal lymphocyte development. Here we show that in murine lymphocytes these physiological DNA breaks activate a broad transcriptional program. This program transcends the canonical DNA double-strand break response and includes many genes that regulate diverse cellular processes important for lymphocyte development. Moreover, the expression of several of these genes is regulated similarly in response to genotoxic DNA damage. Thus, physiological DNA double-strand breaks provide cues that can regulate cell-type-specific processes not directly involved in maintaining the integrity of the genome, and genotoxic DNA breaks could disrupt normal cellular functions by corrupting these processes.


systematic_name: M6023
exact_source: Table 1S
source_species_code: MM
GEO_id: GSE9024
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in pre B lymphocyte after induction of physiological DNA double-strand breaks (DSB) by RAG2 [GeneID=5897]; the changes are independent of ATM [GeneID=472] signaling.

description_full:
  DNA double-strand breaks are generated by genotoxic agents and by cellular endonucleases as intermediates of several important physiological processes. The cellular response to genotoxic DNA breaks includes the activation of transcriptional programs known primarily to regulate cell-cycle checkpoints and cell survival. DNA double-strand breaks are generated in all developing lymphocytes during the assembly of antigen receptor genes, a process that is essential for normal lymphocyte development. Here we show that in murine lymphocytes these physiological DNA breaks activate a broad transcriptional program. This program transcends the canonical DNA double-strand break response and includes many genes that regulate diverse cellular processes important for lymphocyte development. Moreover, the expression of several of these genes is regulated similarly in response to genotoxic DNA damage. Thus, physiological DNA double-strand breaks provide cues that can regulate cell-type-specific processes not directly involved in maintaining the integrity of the genome, and genotoxic DNA breaks could disrupt normal cellular functions by corrupting these processes.


systematic_name: M2831
exact_source: Table 2S
source_species_code: MM
GEO_id: GSE9024
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in pre B lymphocyte after induction of physiological DNA double-strand breaks (DSB) by RAG2 [GeneID=5897]; the changes depend on ATM [GeneID=472] but not NFKB signaling.

description_full:
  DNA double-strand breaks are generated by genotoxic agents and by cellular endonucleases as intermediates of several important physiological processes. The cellular response to genotoxic DNA breaks includes the activation of transcriptional programs known primarily to regulate cell-cycle checkpoints and cell survival. DNA double-strand breaks are generated in all developing lymphocytes during the assembly of antigen receptor genes, a process that is essential for normal lymphocyte development. Here we show that in murine lymphocytes these physiological DNA breaks activate a broad transcriptional program. This program transcends the canonical DNA double-strand break response and includes many genes that regulate diverse cellular processes important for lymphocyte development. Moreover, the expression of several of these genes is regulated similarly in response to genotoxic DNA damage. Thus, physiological DNA double-strand breaks provide cues that can regulate cell-type-specific processes not directly involved in maintaining the integrity of the genome, and genotoxic DNA breaks could disrupt normal cellular functions by corrupting these processes.


systematic_name: M3644
exact_source: Table 2S
source_species_code: MM
GEO_id: GSE9024
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in pre B lymphocyte after induction of physiological DNA double-strand breaks (DSB) by RAG2 [GeneID=5897]; the changes depend on ATM [GeneID=472] but not NFKB signaling.

description_full:
[cell repeats an earlier one in this file: 1163 characters]


systematic_name: M1848
exact_source: Table 1AS-1CS
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by skin tumor promoters but completely blocked by expression of TAM67, a dominan-negative form of JUN [GeneID=3725].

description_full:
  Activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB)-dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFkappaB activation by interacting with NFkappaB p65. Two-stage [7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14-HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67-expressing mice results in dramatic inhibition of tumor promoter-induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPA- or E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1- and/or NFkappaB-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA-induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NFkappaB sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter.


systematic_name: M1850
exact_source: Table 2S
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Known targets of AP1 that were down-regulated by overexpression of TAM67, a dominant-negative form of JUN [GeneID=3725].

description_full:
  Activation of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB)-dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NFkappaB activation by interacting with NFkappaB p65. Two-stage [7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14-HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67-expressing mice results in dramatic inhibition of tumor promoter-induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPA- or E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1- and/or NFkappaB-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA-induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NFkappaB sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter.


systematic_name: M1852
exact_source: Table 2: Plasmacytic
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes that best disciminate plasmablastic plasmacytoma from plasmacytic plasmacytoma tumors.

description_full:
  We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V(+) congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJL-beta2M(-/-) mice. NFS.V(+) tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to immunoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V(+) and SJL-beta2M(-/-) mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease.


systematic_name: M8701
exact_source: Fig. 3bS
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in naive T lymphocytes lacking FURIN [GeneID=5045]: Cre-Lox knockout of FURIN in CD4+ [GeneID=920] cells.

description_full:
  West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.


systematic_name: M19384
exact_source: Supplmentary File 2: pvalue<0.05 and log2(Fold Change) > 1.5
source_species_code: MM
GEO_id: GSE11981
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mouse stroma of pancreatic adenocarcinoma zenografts after treatment with HhAntag, a hedgehog (Hh) pathway inhibitor.

description_full:
  Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.


systematic_name: M1866
exact_source: Table 2S: Invasive/general =< 0.5
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the subpopulation of invasive PyMT cells (breast cancer) compared to the general population of PyMT cells.

description_full:
  Correlating tumor cell behavior in vivo with patterns of gene expression has led to new insights into the microenvironment of tumor cells in the primary tumor. Until now, these studies have been done with cell line-derived tumors. In the current study, we have analyzed, in polyoma middle T oncogene (PyMT)-derived mammary tumors, tumor cell behavior and gene expression patterns of the invasive subpopulation of tumor cells by multiphoton-based intravital imaging and microarray-based expression profiling, respectively. Our results indicate that the patterns of cell behavior that contribute to invasion and metastasis in the PyMT tumor are similar to those seen previously in rat MTLn3 cell line-derived mammary tumors. The invasive tumor cells collected from PyMT mouse mammary tumors, like their counterparts from rat xenograft mammary tumors, are a population that is relatively nondividing and nonapoptotic but chemotherapy resistant and chemotactic. Changes in the expression of genes that occur uniquely in the invasive subpopulation of tumor cells in the PyMT mammary tumors that fall on the Arp2/3 complex, capping protein and cofilin pathways show a pattern like that seen previously in invasive tumor cells from the MTLn3 cell line-derived tumors. These changes predict an enhanced activity of the cofilin pathway, and this was confirmed in isolated invasive PyMT tumor cells. We conclude that changes in gene expression and their related changes in cell behavior, which were identified in the invasive tumor cells of cell line-derived tumors, are conserved in the invasive tumor cells of PyMT-derived mouse mammary tumors, although these tumor types have different genetic origins.


systematic_name: M1867
exact_source: Table 3A
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Selected genes changed in NMuMG cells (mammary epithelium) transformed by overexpression of CCND1 [GeneID=595] vs those transformed by overexpression of CCND1 and MYC [GeneID=4609].

description_full:
  Cyclin D1 is one of the most commonly overexpressed oncogenes in breast cancer; yet, it is not clear whether cyclin D1 alone is capable of causing malignant transformation of mammary epithelial cells. Here, we show that ectopic expression of cyclin D1 in benign mouse mammary epithelial cells promotes cell proliferation, anchorage-independent growth in soft agar, and tumorigenesis in severe combined immunodeficient mice. To address the possible interaction of cyclin D1 and c-myc in malignant transformation, we used cyclin D1/c-myc dual-expressing clones, which displayed more aggressive and invasive phenotype than cyclin D1-expressing clones. These data provide evidence that overexpression of cyclin D1 or coexpression with c-myc could cause invasive malignant transformation of benign mouse mammary epithelial cells. Furthermore, microarray analysis of cyclin D1 and cyclin D1/c-myc clones showed that these two tumor-producing clones might use distinct invasive pathways. In summary, overexpression of cyclin D1 may commit mammary epithelia to a tumor-prone phenotype in which cooperation with other genes, such as synergy with c-myc, may lead to a more aggressive phenotype.


systematic_name: M10694
exact_source: Table 2S: log-ratio > 0
source_species_code: MM
GEO_id: GSE7212
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in medulloblastoma tumors from heterozygotic CXCR6 [GeneID=10663] knockout mice compared to those from PTCH1 [GeneID=5727] heterozygotic knockout mice.

description_full:
  The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes.


systematic_name: M17228
exact_source: Table 2S: log-ratio < 0
source_species_code: MM
GEO_id: GSE7212
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in medulloblastoma tumors from heterozygotic CXCR6 [GeneID=10663] knockout mice compared to those from PTCH1 [GeneID=5727] heterozygotic knockout mice.

description_full:
  The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes.


systematic_name: M1367
exact_source: Fig 1S: cluster 1
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes from cluster 1: up-regulated in group C of tumors arising from overexpression of BCL2L1 and MYC [GeneID=598;4609] in plasma cells.

description_full:
  Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. We have previously shown that the targeted expression of the transgenes c-Myc and Bcl-X(L) in murine plasma cells produces malignancy that displays features of human myeloma, such as localization of tumor cells to the bone marrow and lytic bone lesions. We have isolated and characterized in vitro cultures and adoptive transfers of tumors from Bcl-xl/Myc transgenic mice. Tumors have a plasmablastic morphology and variable expression of CD138, CD45, CD38, and CD19. Spectral karyotyping analysis of metaphase chromosomes from primary tumor cell cultures shows that the Bcl-xl/Myc tumors contain a variety of chromosomal abnormalities, including trisomies, translocations, and deletions. The most frequently aberrant chromosomes are 12 and 16. Three sites for recurring translocations were also identified on chromosomes 4D, 12F, and 16C. Gene expression profiling was used to identify differences in gene expression between tumor cells and normal plasma cells (NPC) and to cluster the tumors into two groups (tumor groups C and D), with distinct gene expression profiles. Four hundred and ninety-five genes were significantly different between both tumor groups and NPCs, whereas 124 genes were uniquely different from NPCs in tumor group C and 204 genes were uniquely different from NPCs in tumor group D. Similar to human myeloma, the cyclin D genes are differentially dysregulated in the mouse tumor groups. These data suggest the Bcl-xl/Myc tumors are similar to a subset of plasmablastic human myelomas and provide insight into the specific genes and pathways underlying the human disease.


