Gut stem cell necroptosis by genome instability triggers bowel inflammation

Posted: 2020-03-30   Visits: 475

Abstract: The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay  between heredity and environment 1,2. Here we report that deficiency in SETDB1, a  histone methyltransferase that mediates the trimethylation of histone H3 at  lysine 9, participates in the pathogenesis of IBD. We found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in  intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1  safeguards genome stability3, and the loss of SETDB1 in intestinal stem cells  released repression of endogenous retroviruses (retrovirus-like elements with  long repeats that, in humans, comprise approximately 8% of the genome). Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein 1(ZBP1)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation.  Genome instability, reactive endogenous retroviruses, upregulation of ZBP1 and  necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of  RIP3 showed a curative effect in SETDB1-deficient mice, which suggests that  targeting necroptosis of intestinal stem cells may represent an approach for the  treatment of severe IBD.