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.

中文翻译：

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SUV39H1 的氧化还原敏感性表观遗传激活导致肝缺血再灌注损伤


肝缺血再灌注 （I/R） 损伤是一个临床相关的病理生理过程，它决定了挽救生命的肝移植的有效性，其中异常的 ROS 积累起着关键作用。在本研究中，我们研究了赖氨酸甲基转移酶 SUV39H1 在此过程中的作用，重点关注调节机制和翻译潜力。我们报道，SUV39H1 在缺血再灌注小鼠的肝组织和暴露于缺氧再氧合 （H/R） 的肝细胞中以氧化还原敏感的方式上调。从机制上讲，共激活因子相关精氨酸甲基转移酶 1 （CARM1） 通过促进组蛋白 H3R17 甲基化介导氧化还原敏感的 Suv39h1 反式激活。始终如一，药物 CARM1 抑制减轻了肝脏 I/R 损伤。此外，整体或肝细胞条件性 Suv39h1 KO 小鼠免受肝脏 I/R 损伤。RNA-seq 显示醛脱氢酶 1 家族 1a （Aldh1a1） 是 SUV39H1 的新靶点。SUV39H1直接与 Aldh1a1 启动子结合并抑制 H/R 攻击肝细胞中的 Aldh1a1 转录。ALDH1A1沉默消除了 SUV39H1 缺乏对 H/R 损伤的保护作用，而ALDH1A1过度表达减轻了小鼠的肝脏 I/R 损伤。重要的是，小分子 SUV39H1 抑制剂的给药实现了与 SUV39H1 缺失相似的保肝效果。最后，在人类肝脏 I/R 标本中观察到 Suv39h1 表达增加和 Aldh1a1 表达降低。总之，我们的数据揭示了 SUV39H1 在肝脏 I/R 损伤中的调节作用，并作为概念验证，靶向 SUV39H1-ALDH1A1 轴可能被认为是干预肝脏 I/R 损伤的合理方法。