2. Academic Validation
  3. YAP represses intestinal inflammation through epigenetic silencing of JMJD3

YAP represses intestinal inflammation through epigenetic silencing of JMJD3

  • Clin Epigenetics. 2024 Jan 20;16(1):14. doi: 10.1186/s13148-024-01626-w.
Hua Zhu # 1 2,  Jiali Lu # 1 2,  MingYue Fu 1 2,  Ping Chen 1 2,  Yali Yu 1 2,  Min Chen 1 2,  Qiu Zhao 1 2,  Min Wu 3,  Mei Ye 4 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China.
  • 2 Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China.
  • 3 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Intestinal and Colorectal Diseases, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China.
  • 4 Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China. [email protected].
  • 5 Hubei Clinical Centre and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, 430071, Hubei, China. [email protected].
  • # Contributed equally.
PMID: 38245781 DOI: 10.1186/s13148-024-01626-w
Abstract

Background: Epigenetics plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Some studies have reported that YAP is involved in inflammatory response and can regulate target genes through epigenetic modifications. JMJD3, a histone H3K27me3 demethylase, is associated with some inflammatory diseases. In this study, we investigated the role of YAP in the development of IBD and the underlying epigenetic mechanisms.

Results: YAP expression was significantly increased in both in vitro and in vivo colitis models as well as in patients with IBD. Epithelial-specific knockout of YAP aggravates disease progression in dextran sodium sulfate (DSS)-induced murine colitis. In the TNF-α-activated cellular inflammation model, YAP knockdown significantly increased JMJD3 expression. Coimmunoprecipitation experiments showed that YAP and EZH2 bind to each other, and chromatin immunoprecipitation-PCR (ChIP-PCR) assay indicated that silencing of YAP or EZH2 decreases H3K27me3 enrichment on the promoter of JMJD3. Finally, administration of the JMJD3 pharmacological inhibitor GSK-J4 alleviated the progression of DSS-induced murine colitis.

Conclusion: Our findings elucidate an epigenetic mechanism by which YAP inhibits the inflammatory response in colitis through epigenetic silencing of JMJD3 by recruiting EZH2.

Keywords

Hippo pathway; Histone modification; IBD; JMJD3; YAP.

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