Redox-sensitive epigenetic activation of SUV39H1 contributes to liver ischemia-reperfusion injury

Zilong Li; Jichen Li; Meng Wu; Zexin Li; Jiawen Zhou; Yunjie Lu; Yong Xu; Lei Qin; Zhiwen Fan

doi:10.1016/j.redox.2024.103414

Redox-sensitive epigenetic activation of SUV39H1 contributes to liver ischemia-reperfusion injury

Redox Biol. 2024 Oct 31:78:103414. doi: 10.1016/j.redox.2024.103414. Online ahead of print.

Authors

Zilong Li¹, Jichen Li², Meng Wu², Zexin Li², Jiawen Zhou², Yunjie Lu³, Yong Xu⁴, Lei Qin⁵, Zhiwen Fan⁶

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University, Jinan, China. Electronic address: zlli@sdfmu.edu.cn.
² State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
³ Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China.
⁴ State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research, College of Agriculture and Biology, Liaocheng University, Liaocheng, China. Electronic address: yjxu@cpu.edu.cn.
⁵ Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: qinlei@suda.edu.cn.
⁶ Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China. Electronic address: fanzhiwenfff@126.com.

PMID: 39603205
DOI: 10.1016/j.redox.2024.103414

Abstract

Liver ischemia-reperfusion (I/R) injury is a clinically relevant pathophysiological process that determines the effectiveness of life-saving liver transplantation, to which aberrant ROS accumulation plays a key role. In the present study we investigated the role of SUV39H1, a lysine methyltransferases, in this process focusing on regulatory mechanism and translational potential. We report that SUV39H1 expression was up-regulated in the liver tissues of mice subjected to ischemia-reperfusion and in hepatocytes exposed to hypoxia-reoxygenation (H/R) in a redox-sensitive manner. Mechanistically, coactivator associated arginine methyltransferases 1 (CARM1) mediated redox-sensitive Suv39h1 trans-activation by promoting histone H3R17 methylation. Consistently, pharmaceutical CARM1 inhibition attenuated liver I/R injury. In addition, global or hepatocyte conditional Suv39h1 KO mice were protected from liver I/R injury. RNA-seq revealed that aldehyde dehydrogenase 1 family 1a (Aldh1a1) as a novel target for SUV39H1. SUV39H1 directly bound to the Aldh1a1 promoter and repressed Aldh1a1 transcription in H/R-challenged hepatocytes. ALDH1A1 silencing abrogated the protective effects of SUV39H1 deficiency on H/R-inflicted injuries whereas ALDH1A1 over-expression mitigated liver I/R injury in mice. Importantly, administration of a small-molecule SUV39H1 inhibitor achieved similar hepatoprotective effects as SUV39H1 deletion. Finally, increased Suv39h1 expression and decreased Aldh1a1 expression were observed in liver I/R specimens in humans. In conclusion, our data uncover a regulatory role for SUV39H1 in liver I/R injury and serve as proof-of-concept that targeting the SUV39H1-ALDH1A1 axis might be considered as a reasonable approach for the intervention of liver I/R injury.

Keywords: Epigenetics; Hepatocyte; Ischemia-reperfusion; Redox homeostasis; Transcriptional regulation.