2. Academic Validation
  3. Gut stem cell necroptosis by genome instability triggers bowel inflammation

Gut stem cell necroptosis by genome instability triggers bowel inflammation

  • Nature. 2020 Apr;580(7803):386-390. doi: 10.1038/s41586-020-2127-x.
Ruicong Wang  # 1 2,  Hongda Li  # 1 2,  Jianfeng Wu  # 1 2,  Zhi-Yu Cai  # 1 2,  Baizhou Li 3,  Hengxiao Ni 1 2,  Xingfeng Qiu 4,  Hui Chen 5,  Wei Liu 1 2,  Zhang-Hua Yang 1 2,  Min Liu 1 2,  Jin Hu 1 2,  Yaoji Liang 1,  Ping Lan 6,  Jiahuai Han 7 8,  Wei Mo 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • 2 Cancer Research Center, Xiang'an Hospital, School of Medicine, Xiamen University, Xiamen, China.
  • 3 Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Department of Gastrointestinal Surgery, Zhong Shan Hospital, Xiamen University, Xiamen, China.
  • 5 Department of Gastroenterology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 6 Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 7 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China. jhan@xmu.edu.cn.
  • 8 Cancer Research Center, Xiang'an Hospital, School of Medicine, Xiamen University, Xiamen, China. jhan@xmu.edu.cn.
  • 9 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China. wmo@xmu.edu.cn.
  • 10 Cancer Research Center, Xiang'an Hospital, School of Medicine, Xiamen University, Xiamen, China. wmo@xmu.edu.cn.
  • # Contributed equally.
PMID: 32296174 DOI: 10.1038/s41586-020-2127-x
Abstract

The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay between heredity and environment1,2. 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.

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