Gut stem cell necroptosis by genome instability triggers bowel inflammation

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 () and Wei Mo ()
Additional contact information
Ruicong Wang: Xiamen University
Hongda Li: Xiamen University
Jianfeng Wu: Xiamen University
Zhi-Yu Cai: Xiamen University
Baizhou Li: The Second Affiliated Hospital of Zhejiang University School of Medicine
Hengxiao Ni: Xiamen University
Xingfeng Qiu: Xiamen University
Hui Chen: The First Affiliated Hospital of Fujian Medical University
Wei Liu: Xiamen University
Zhang-Hua Yang: Xiamen University
Min Liu: Xiamen University
Jin Hu: Xiamen University
Yaoji Liang: Xiamen University
Ping Lan: Sun Yat-sen University
Jiahuai Han: Xiamen University
Wei Mo: Xiamen University

Nature, 2020, vol. 580, issue 7803, 386-390

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2127-x Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:580:y:2020:i:7803:d:10.1038_s41586-020-2127-x

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2127-x

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().