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Setdb1 safeguards genome stability against stem cell necroptosis and bowel inflammation (RNA-seq)

ABSTRACT: The aetiology of bowel inflammatory disease (IBD) is a multifactorial interplay between heredity and environment1-3. Here we report SETDB1, a histone methyltransferase (HMTs) for histone H3 lysine 9 trimethylation (H3K9me3) whose deficiency participates in the pathogenesis of IBD. We found that SETDB1 level decreased in IBD patients and that mice with reduced SETDB1 in intestinal stem cells (ISCs) developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability4, of which the loss in ISCs released repression of endogenous retrovirus (ERVs), the retrovirus-like elements with long repeats that comprise ~8% of genome5. Excessive viral mimicry generated by motivated ERVs triggered Z-DNA-binding protein 1 (ZBP1) dependent necroptosis, which irreversibly disrupted the homeostasis of epithelial barrier and promoted bowel inflammation. Of note, genome instability, reactive ERVs, upregulation of ZBP1 and necroptosis were seen in IBD patients. Pharmaceutic inhibition of RIP3 showed curative effect in SETDB1 deficient mice, suggesting therapy targeting ISC necroptosis may represent a new approach for severe IBD treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE129172 | GEO | 2020/01/01

REPOSITORIES: GEO

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SETDB1 safeguards genome stability against necroptosis and bowel inflammation (ChIP-seq)

Project description:The aetiology of bowel inflammatory disease (IBD) is a multifactorial interplay between heredity and environment1-3. Here we report SETDB1, a histone methyltransferase (HMTs) for histone H3 lysine 9 trimethylation (H3K9me3) whose deficiency participates in the pathogenesis of IBD. We found that SETDB1 level decreased in IBD patients and that mice with reduced SETDB1 in intestinal stem cells (ISCs) developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability4, of which the loss in ISCs released repression of endogenous retrovirus (ERVs), the retrovirus-like elements with long repeats that comprise ~8% of genome5. Excessive viral mimicry generated by motivated ERVs triggered Z-DNA-binding protein 1 (ZBP1) dependent necroptosis, which irreversibly disrupted the homeostasis of epithelial barrier and promoted bowel inflammation. Of note, genome instability, reactive ERVs, upregulation of ZBP1 and necroptosis were seen in IBD patients. Pharmaceutic inhibition of RIP3 showed curative effect in SETDB1 deficient mice, suggesting therapy targeting ISC necroptosis may represent a new approach for severe IBD treatment.

2020-01-01 | GSE129173 | GEO

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SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes [RNA-Seq]

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2024-05-25 | GSE242865 | GEO

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ZBP1-MLKL-dependent Necroptosis Triggers STING-mediated Cytosolic DNA Sensing and Promotes Antitumor Immunity of Radiation

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Programmed necrosis and apoptosis differentially regulate cancer development and biliary homeostasis in the liver

Project description:For years, the term apoptosis was used synonymously for programmed cell death. However, it was recently discovered that programmed necrosis M-bM-^@M-^S dependent on the kinases Receptor-Interacting-Protein-Kinase (RIP)1 and RIP3 (also called necroptosis) M-bM-^@M-^S represents a major programmed cell-death pathway in development and immunity. At present, the functions of necroptosis in hepatitis, liver cancer development and biliary disease are unclear. Here we show that in mice with chronic hepatitis due to conditional ablation of TGF-beta-activated kinase1 (TAK1) in liver parenchymal cells (LPC), both apoptotic and necroptotic signaling pathways are activated. Strikingly, only Caspase-8-dependent apoptosis promotes spontaneous liver cancer development, while in contrast LPC necroptosis inhibits hepatic tumourigenesis. The tumour-promoting effect of apoptosis results from an induction of strong compensatory proliferation of LPC, linked with the paracrine action of growth factors like Insulin-like growth factor-2 (IGF-2) not induced by necroptosis. In addition to prevention of HCC development, induction of necroptosis leads to massive cholestasis and hyperbilirubinemia, resulting from an insufficient ductular reaction and biliary regeneration from the hepatic stem cell niche as a response to chronic hepatitis. These results indicate previously undefined distinctive functions of apoptosis and programmed necrosis in controlling cancer development and cholestasis in the liver with important implications for future therapeutic strategies in chronic liver disease. 8 samples were analysed. We compared groups of 4 Tak1/Caspase8 LPC double knockout mice and 4 Tak1 LPC-KO/Rip3-/- mice to detect genes differentially regulated by apoptotic and necrotic signalling pathways.

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DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements and chimaeric transcripts in mouse ES cells

Project description:DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3) play important roles in silencing of genes and retroelements. However, a comprehensive comparison of genes and repetitive elements repressed by these pathways has not been reported. Here we show that in mouse embryonic stem cells (mESCs), the genes up-regulated following deletion of the H3K9 methyltransferase Setdb1 are distinct from those de-repressed in mESC deficient in the DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b, with the exception of a small number of primarily germline-specific genes. Numerous endogenous retroviruses (ERVs) lose H3K9me3 and are concomitantly de-repressed exclusively in SETDB1 knockout mESCs. Strikingly, ~15% of up-regulated genes are induced in association with de-repression of promoter proximal ERVs, half in the context of "chimaeric" transcripts that initiate within these retroelements and splice to genic exons. Thus, SETDB1 plays a previously unappreciated yet critical role in inhibiting aberrant gene transcription by suppressing the expression of proximal ERVs. NChIP-seq and mRNA-seq of WT, SETDB1 KO and DMNT1 TKO mESCs

2011-05-21 | E-GEOD-29413 | biostudies-arrayexpress

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