Inactivation of Irf1 causes susceptibility to colitis-associated colorectal cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA478321 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7447020_1.fastq.gz | Fastqsanger.gz | |||
| SRR7447020_2.fastq.gz | Fastqsanger.gz | |||
| SRR7447030_1.fastq.gz | Fastqsanger.gz | |||
| SRR7447030_2.fastq.gz | Fastqsanger.gz | |||
| SRR7447021_1.fastq.gz | Fastqsanger.gz |
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Project description:The incidence of colorectal cancer (CRC) is increased in patients afflicted by inflammatory bowel diseases (IBD) The cellular and molecular mechanisms that link chronic inflammation of the gut and increased CRC susceptibility are poorly understood. Risk of IBD is strongly influenced by genetic factors, including the IBD5 locus (5q31), harboring the IRF1 gene. A cause to effect relationship between chronic inflammation and CRC, and a possible role of IRF1 were studied in Irf1-/- mutant mice in a model of colitis associated CRC (CA-CRC) induced by azoxymethane and the irritant dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation, enhanced crypt cells proliferation and reduced tissue repair in Irf1-/- mutants, and this prior to appearance of tumors. A considerable infiltration of leukocytes is seen at this early stage in Irf1-/- colons, this infiltrate being composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells, mast cells, and CD3+ lymphoid cells. Studies in bone marrow chimeras show that differential susceptibility to CA-CRC of Irf1-/- vs. B6 controls is fully transferable by hematopoietic cells. Studies in human datasets confirm that transcripts signatures seen in Irf1-/- mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with CRC. In addition, IRF1 expression in the colon is significantly decreased in late stage CRC (stages 3, 4) associated with poorer prognosis. These studies suggest that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ in gut establishing microbial-driven chronic inflammation and possibly creating a tumor promoting environment.
2019-10-31 | GSE116374 | GEO
Project description:Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1?/? MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis. RNA was isolated from RasV12 transformed NIH/3T3 cells (RasV12 cells) treated with 20?M U0126 or 500U/ml IFN-?, or left untreated, for 6 hours, triplicate biological samples (9 samples).
2014-11-13 | E-GEOD-49469 | biostudies-arrayexpress
Project description:The mechanisms linking chronic inflammation of the gut (IBD) and increased colorectal cancer susceptibility are poorly understood. IBD risk is influenced by genetic factors, including the IBD5 locus (human 5q31), that harbors the IRF1 gene. A cause-to-effect relationship between chronic inflammation and colorectal cancer, and a possible role of IRF1 were studied in Irf1-/- mice in a model of colitis-associated colorectal cancer (CA-CRC) induced by azoxymethane and dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation and enhanced enterocyte proliferation in Irf1-/- mutants, prior to appearance of tumors. Considerable infiltration of leukocytes is seen in Irf1-/- colons at this early stage, and is composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells and other granulocytes, as well as CD4+ lymphoid cells. Differential susceptibility to CA-CRC of Irf1-/- vs. B6 controls is fully transferable through hematopoietic cells as observed in bone marrow chimera studies. Transcript signatures seen in Irf1-/- mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with colorectal cancer. In addition, IRF1 expression in the colon is significantly decreased in late stage colorectal cancer (stages 3, 4) and is associated with poorer prognosis. This suggests that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ during chronic inflammation, possibly via the creation of a tumor-promoting environment.
| S-EPMC6906452 | biostudies-literature
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.
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.
2016-03-07 | GSE77884 | GEO
Project description:Background and Aims: In the interleukin-10-deficient (Il10-/-) mouse model of IBD, 10 quantitative trait loci (QTL) have been shown to be associated with colitis susceptibility by linkage analyses on experimental crosses of highly susceptible C3H/HeJBir (C3Bir)-Il10-/- and partially resistant C57BL/6J (B6)-Il10-/- mice. The strongest locus (C3Bir-derived cytokine deficiency-induced colitis susceptibility [Cdcs]1 on Chromosome [Chr] 3) controlled multiple colitogenic subphenotypes and contributed the vast majority to the phenotypic variance in cecum and colon. This was demonstrated by interval-specific Chr 3 congenic mice wherein defined regions of Cdcs1 from C3Bir or B6 were bred into the IL-10-deficient reciprocal background and altered the susceptible or resistant phenotype. Furthermore, this locus likely acts by inducing innate hypo- and adaptive hyperresponsiveness, associated with impaired NFΚB responses of macrophages. The aim of the present study was to dissect the complexity of Cdcs1 by further development and characterization of reciprocal Cdcs1 congenic strains and to identify potential candidate genes in the congenic interval. Material and Methods: In total, 15 reciprocal congenic strains were generated from Il10-/- mice of either C3H/HeJBir or C57BL/6J backgrounds by 10 cycles of backcrossing. Colitis activity was monitored by histological grading. Candidate genes were identified by fine mapping of congenic intervals, sequencing, microarray analysis and a high-throughput real-time RT-PCR approach using bone marrow-derived macrophages. Results: Within the originally identified Cdcs1-interval, three independent regions were detected that likely contain susceptibility-determining genetic factors (Cdcs1.1, Cdcs1.2, and Cdcs1.3). Combining results of candidate gene approaches revealed Fcgr1, Cnn3, Larp7, and Alpk1 as highly attractive candidate genes with polymorphisms in coding or regulatory regions and expression differences between susceptible and resistant mouse strains. Conclusions: Subcongenic analysis of the major susceptibility locus Cdcs1 on mouse chromosome 3 revealed a complex genetic structure. Candidate gene approaches revealed attractive genes within the identified regions with homologs that are located in human susceptibility regions for IBD.
2009-10-01 | GSE15318 | GEO
Project description:CCDC88B is a risk factor for several chronic inflammatory diseases in humans and its inactivation causes a migratory defect in DCs in mice. CCDC88B belongs to a family of cytoskeleton-associate scaffold proteins that feature protein:protein interaction domains. Here, we identified the Rho/Rac Guanine Nucleotide Exchange Factor 2 (ARHGEF2) and the RAS Protein Activator Like 3 (RASAL3) as CCDC88B physical and functional interactors. Mice defective in Arhgef2 or Rasal3 show dampene neuroinflammation, and display altered cellular response and susceptibility to colitis; ARHGEF2 maps t a human Chromosome 1 locus associated with susceptibility to IBD. Arhgef2 and Rasal3 mutant DCs show altered migration and motility in vitro, causing either reduced (Arhgef2) or enhanced (Rasal3) migratory properties. The CCDC88B/RASAL3/ARHGEF2 complex appears to regulate DCs migration by modulating activation of RHOA, with ARHGEF2 and RASAL3 acting in opposite regulatory fashions, providing a molecular mechanism for the involvement of these proteins in DCs immune functions.
2024-01-17 | GSE249342 | GEO
Project description:Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1−/− MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis.
2014-11-13 | GSE49469 | GEO
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, whereas inborn errors of IFN-a/b immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-a/b immunity. The IRF1-dependent cellular responses to IFN-γ are, both quantitatively and qualitatively, much greater than those to IFN-a/b in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-γ. By contrast, cell-intrinsic IFN-a/b immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-a/b immunity. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in myeloid cells.
2023-01-19 | PXD037759 | Pride
Project description:Background: The etiology of Inflammatory Bowel Disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3 and Reg3 independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that five weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or healthy microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for the host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.
2024-05-01 | GSE262585 | GEO