GSE129172
Setdb1 safeguards genome stability against stem cell necroptosis and bowel inflammation (RNA-seq)
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. Overall design: Crypts mRNA profiles of 8-weeks old wild type (setdb1fl/fl) and setdb1-iIEC-KO mice were generated by deep sequencing using BGI-500. ISC total mRNA from Lgr5–EGFP–ires–CreERT2;setdb1fl/+ and Lgr5–EGFP–ires–CreERT2;setdb1fl/fl  were generated for deep sequencing using Hiseq X10.