IFN-γ stimulation induces immunosuppression in CRC
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252712 | GEO | 2024/01/22
REPOSITORIES: GEO
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Project description:The cancer stem cell (CSC) state is intimately associated with suppression of the immune tumor microenvironment (TME). The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) CSCs in association with induction of the BAF, NuRD and PBAF chromatin remodeling complexes. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN- pathway in CRPC cells. We show that the MUC1-CARID1A/BAF pathway induces IFNGR1 transcription and that MUC1-CNuRD signaling suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. Additionally and in contrast, our results demonstrate that MUC1-C and the PBRM1/PBAF pathway are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune TME, and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Consistent with these results, MUC1 associates with immune cell-depleted “cold” CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-G pathway with induction of chromatin remodeling complexes in linking CSC dedifferentiation and immune evasion.
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Project description:Aims and methods: To analyze how IFNγ induces coding and non-coding nascent transcriptional changes, SNU-seq is used to measure genome-wide changes in nascent transcription in untreated, 0.5hr, 2hr and 24hr IFNγ treated Hep3B cells. SNU-seq identifies the last transcribed nucleotide at near single-nucleotide resolution. 3'-end RNA-seq is used to examine RNA levels. ChIPmentation and ATAC-seq are used to assess the differential chromatin landscape upon IFNγ treatments, measuring H3K27ac, H3K4me3 and CTCF genome-wide changes as well as DNA accessibility in untreated, 0.5hr, 2hr and 24hr IFNγ treated Hep3B cells. Higher-order chromatin structure is investigated upon IFNγ treatments using Capture-C to measure promoter interactions of three gene promoters; IRF1, STAT1, and CD274. Results: 3'-end RNA-seq reveals IFNγ stimulated genes. SNU-seq identifies dynamic transcription at genes and non-coding intergenic regions and is used to demonstrate differential APA upon IFNγ treatments. By measuring transcription at nucleosome depleted regions, differential enhancer activity was demonstrated. IFNγ induces hundreds of methylation changes and thousands of acetylation changes over 24hrs. Unlike H3K4me3 which is deposited at late timepoints, H3K27ac is dynamically deposited. This acetylation is sometimes sustained throughout 24hrs but is often transiently deposited. CTCF shows very few binding changes throughout the timecourse. IFNγ induces significant changes in promoter:enhancer interactions at IRF1 and STAT1. The CD274 promoter loops to the nearest gene promoter; PLGRKT.
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Project description:Identifying interactors of IRF1 and STAT1 in bone marrow-derived macrophages during type I and type II interferon treatment using the proximity-dependent labeling approach TurboID followed by Mass Spectrometry
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2016-03-07 | GSE77885 | GEO
Project description:IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by pro-inflammatory signals such as interferon gamma. Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type, and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all the genes bound by (cistromes) and transcriptionally activated (regulomes) by IRF8, IRF1, PU.1 and STAT1 including modulation of epigenetic histone marks. Of seven binding combinations identified, two (cluster 1: IRF8/IRF1/STAT1/PU.1; cluster 5: IRF1/STAT1/PU.1) were found to have a major role in controlling macrophage transcriptional programs both at basal level and following IFNγ activation. They direct expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and anti-microbial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immuno-deficiencies, and with loci associated for several inflammatory diseases in humans.
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Project description:B16 Mouse melanoma cells (MO5) grow in syngeneic C57BL/6 mice. Anti-PD-1 Ab as an Immunecheck point inhibitor and/or metformin were administered on day 7 after tumor inoculation to mice. The tumor growth was decreased by either anti-PD-1 Ab or metformin treatment. Anti- tumor effect was more pronounced by the combination therapy of anti-PD-1 Ab and metformin. The mechanism underlying the superior effect of the combination therapy to mono-therapies were investigated by RNA sequencing of tumor infiltrating CD8+ cells (CD8TILs) and tumor cells. As a result, CD8TILs with the combination therapy was found to express IFNg and GzmB and to activate IRF1/8, STAT1/2, NFkB, TBX21. Moreover, tumor cells were found to activate IRF1/8, STAT1/2, NFkB, indicating that tumor cells sharply responded to IFNg produced from CD8TILs. The IFNg was also found to downregulate metabolism both glycolysis and oxidative phosphorylation (OxPhos) of tumor cells, while it upregulates metabolism of CD8T cells. Collectively, the metabolic competition between CD8TILs and tumor cells was found to shift to the advantage of CD8TILs over tumor cells, resulting in the strong inhibition of tumor growth by the combination therapy of anti-PD-1 Ab and metformin.
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Project description:IRF1, and interferon-induced transcription factor, was found to have antiviral activity against a range of viruses when overexpressed. To determine which genes are associated with expression of IRF1, gene expression analysis was carried out in two different cell line expressing IRF1. The results show that more than 100 genes, many of which overlap with type I interferon-stimulated genes, are induced more than 3-fold by IRF1. A majority of the genes were induced in both cell types, while some genes were highly induced in a cell type-specific manner. To investigate the impact of IRF1 overexpression on the transriptome of two target cell lines, cells were transduced with a lentiviral vector expressing IRF1 or Firefly luciferase (Fluc) as a control. Total mRNA was harvested 48 h post-transduction and processed for Illumina BeadArray analysis. Skin fibroblast cell line described in Dupuis, S. et al., Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33 (3), 388 (2003)
2011-04-01 | E-GEOD-26817 | biostudies-arrayexpress
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (PLS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at PLS of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1/IRF1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
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Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (PLS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at PLS of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1/IRF1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
2023-06-14 | GSE212168 | GEO
Project description:STAT1 and IRF1 are essential effectors of the type I and II interferon (IFN) pathways. Here, we report that the oncogenic MUC1-C protein is necessary for inducing chromatin accessibility and activation of the STAT1 and IRF1 genes in triple-negative breast cancer (TNBC) cells. Our results demonstrate that MUC1-C activates the PBRM1 subunit of the SWI/SNF PBAF chromatin remodeling complex and forms a nuclear complex with PBRM1. We show that MUC1-C associates with PBRM1 and STAT1 on the IRF1 gene at (i) a proximal enhancer-like signature (PLS), and (ii) distal enhancer-like signatures (dELSs). We also show MUC1-C and PBRM1 are necessary for opening chromatin at these signatures and for the induction of IRF1 expression. In extending these results, we found that MUC1-C binds directly to IRF1 and forms nuclear complexes with PBRM1 and IRF1, which are necessary for inducing chromatin accessibility at PLS of the (i) STAT1 gene, (ii) type II IFN pathway IDO1 and WARS genes, and (iii) type I IFN pathway RIG-I, MDA5 and ISG15 genes. Consistent with involvement of chronic inflammation in promoting the cancer stem cell (CSC) state, we show that MUC1-C, PBRM1 and IRF1 are required for self-renewal of TNBC CSCs. Of translational relevance, we report that targeting MUC1-C, PBRM1 and IRF1 circumvents intrinsic DNA damage resistance of TNBC CSCs and that MUC1-C is necessary for acquired resistance to the PARP inhibitor olaparib. These findings demonstrate that MUC1-C activates PBRM1/IRF1 and thereby chromatin remodeling of IFN pathway genes that promote chronic inflammation, the CSC state and DNA damage resistance.
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