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Gut stem cell necroptosis by genome instability triggers bowel inflammation

Author

Listed:
  • Ruicong Wang

    (Xiamen University
    Xiamen University)

  • Hongda Li

    (Xiamen University
    Xiamen University)

  • Jianfeng Wu

    (Xiamen University
    Xiamen University)

  • Zhi-Yu Cai

    (Xiamen University
    Xiamen University)

  • Baizhou Li

    (The Second Affiliated Hospital of Zhejiang University School of Medicine)

  • Hengxiao Ni

    (Xiamen University
    Xiamen University)

  • Xingfeng Qiu

    (Xiamen University)

  • Hui Chen

    (The First Affiliated Hospital of Fujian Medical University)

  • Wei Liu

    (Xiamen University
    Xiamen University)

  • Zhang-Hua Yang

    (Xiamen University
    Xiamen University)

  • Min Liu

    (Xiamen University
    Xiamen University)

  • Jin Hu

    (Xiamen University
    Xiamen University)

  • Yaoji Liang

    (Xiamen University)

  • Ping Lan

    (Sun Yat-sen University)

  • Jiahuai Han

    (Xiamen University
    Xiamen University)

  • Wei Mo

    (Xiamen University
    Xiamen University)

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.

Suggested Citation

  • Ruicong Wang & Hongda Li & Jianfeng Wu & Zhi-Yu Cai & Baizhou Li & Hengxiao Ni & Xingfeng Qiu & Hui Chen & Wei Liu & Zhang-Hua Yang & Min Liu & Jin Hu & Yaoji Liang & Ping Lan & Jiahuai Han & Wei Mo, 2020. "Gut stem cell necroptosis by genome instability triggers bowel inflammation," Nature, Nature, vol. 580(7803), pages 386-390, April.
  • Handle: RePEc:nat:nature:v:580:y:2020:i:7803:d:10.1038_s41586-020-2127-x
    DOI: 10.1038/s41586-020-2127-x
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    Citations

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    Cited by:

    1. Kunkun Zhang & Shaoxuan Chen & Qihua Yang & Shuanghui Guo & Qiang Chen & Zhixiong Liu & Li Li & Mengyun Jiang & Hongda Li & Jin Hu & Xu Pan & Wenbo Deng & Naian Xiao & Bo Wang & Zhan-xiang Wang & Lian, 2022. "The Oligodendrocyte Transcription Factor 2 OLIG2 regulates transcriptional repression during myelinogenesis in rodents," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Jorge Mata-Garrido & Yao Xiang & Yunhua Chang-Marchand & Caroline Reisacher & Elisabeth Ageron & Ida Chiara Guerrera & IƱigo Casafont & Aurelia Bruneau & Claire Cherbuy & Xavier Treton & Anne Dumay & , 2022. "The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Li Weng & Wen-Shuai Tang & Xu Wang & Yingyun Gong & Changqin Liu & Ni-Na Hong & Ying Tao & Kuang-Zheng Li & Shu-Ning Liu & Wanzi Jiang & Ying Li & Ke Yao & Li Chen & He Huang & Yu-Zheng Zhao & Ze-Ping, 2024. "Surplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Haili Bao & Yang Sun & Na Deng & Leilei Zhang & Yuanyuan Jia & Gaizhen Li & Yun Gao & Xinyi Li & Yedong Tang & Han Cai & Jinhua Lu & Haibin Wang & Wenbo Deng & Shuangbo Kong, 2024. "PR-SET7 epigenetically restrains uterine interferon response and cell death governing proper postnatal stromal development," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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