Gut Stem Cell Necroptosis by Genome Instability Triggers Bowel Inflammation

Overview

Journal Nature

Specialty Science

Date 2020 Apr 17

PMID 32296174

Citations 143

Authors

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

Affiliations

Soon will be listed here.

Abstract

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

Citing Articles

SETDB1-Mediated Chromatin Regulation in Intestinal Epithelial Cells During Intestinal Ischemia-Reperfusion Injury.

Higuchi K, Ikenoue M, Ishizuka T, Kai K, Takahashi N, Kubota T Acta Histochem Cytochem. 2025; 58(1):9-18.

PMID: 40060360 PMC: 11886594. DOI: 10.1267/ahc.24-00061.

Targeted delivery of Grem1 and IL-10 separately by mesenchymal stem cells effectively mitigates SETD2-deficient inflammatory bowel disease.

Aji R, Xu Y, Wang Z, Feng W, Gui L, Rao H Theranostics. 2025; 15(6):2215-2228.

PMID: 39990215 PMC: 11840741. DOI: 10.7150/thno.105876.

Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis.

Sun Z, Ye J, Sun W, Jiang L, Shan B, Zhang M Nat Commun. 2025; 16(1):1890.

PMID: 39987261 PMC: 11846980. DOI: 10.1038/s41467-025-57211-z.

New insights into pulmonary arterial hypertension: interaction between PANoptosis and perivascular inflammatory responses.

Su X, Sun Y, Dai A Apoptosis. 2025; .

PMID: 39979525 DOI: 10.1007/s10495-025-02086-0.

Patients with Irritable Bowel Syndrome Exhibit Aberrant Expression of Endogenous Retroviruses and SETDB1.

Tovo P, Ribaldone D, Caviglia G, Calvi C, Montanari P, Tizzani M Cells. 2025; 14(3).

PMID: 39936987 PMC: 11817187. DOI: 10.3390/cells14030196.

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