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
Affiliations
Zilong Li
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; Corresponding author. Shandong First Medical University, Jinan, 250117, China.
Jichen Li
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
Meng Wu
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
Zexin Li
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
Jiawen Zhou
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
Yunjie Lu
Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China
Yong Xu
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; Corresponding authors. China Pharmaceutical University, Nanjing, 211198, China.
Lei Qin
Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China; Corresponding author. the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Zhiwen Fan
Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China; Corresponding authors. Nanjing Drum Tower Hospital, Nanjing, 210009, China.
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.
