ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1.
ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1.
复制标题
ALKBH5 通过 YTHDF1 mRNA 去甲基化调节心肌细胞增殖和心脏再生
作者：
Han Z;Wang X;Xu Z;Cao Y;Gong R;Yu Y;Yu Y;Guo X;Liu S;Yu M;Ma W;Zhao Y;Xu J;Li X;Li S;Xu Y;Song R;Xu B;Yang F;Bamba D;Sukhareva N;Lei H;Gao M;Zhang W;Zagidullin N;Zhang Y;Yang B;Pan Z;Cai B
N6-甲基腺苷（m6 A）RNA修饰是一个动态和可逆的过程，对组织发育和发病至关重要。然而，m6 A在心肌细胞（CM）增殖和心脏再生的调节中的潜在参与仍不清楚。在这项研究中，我们的目的是调查m6 A修饰在出生后和成年损伤的心脏再生中的重要作用。方法与结果：在这项研究中，我们确定了m6 A去甲基化酶ALKBH 5的下调，这是一种m6 A“橡皮擦”，负责增加m6 A甲基化，在出生后的心脏。值得注意的是，ALKBH 5基因敲除小鼠在新生儿心尖切除术后表现出心脏再生能力和心脏功能下降。相反，通过腺相关病毒-9（AAV 9）递送的ALKBH 5强制表达显著减少了幼年（7天）和成年（8周龄）小鼠心肌梗死后的梗死面积，恢复了心脏功能并促进了CM增殖。从机制上讲，ALKBH 5介导的m6 A去甲基化改善了YTH N6-甲基腺苷RNA结合蛋白1（YTHDF 1）的mRNA稳定性，从而增加了其表达，从而促进了Yes相关蛋白（雅普）的翻译。在人诱导多能干细胞衍生的心肌细胞中ALKBH 5和YTHDF 1表达的调节一致地产生了类似的结果。结论：总而言之，我们的研究结果强调了ALKBH 5-m6 A-YTHDF 1-雅普轴在调节CM重新进入细胞周期中的重要作用。这一发现为心脏再生提供了一种新的潜在治疗策略。
N6-methyladenosine (m6A) RNA modification, a dynamic and reversible process, is essential for tissue development and pathogenesis. However, the potential involvement of m6A in the regulation of cardiomyocyte (CM) proliferation and cardiac regeneration remains unclear. In this study, we aimed to investigate the essential role of m6A modification in heart regeneration during postnatal and adult injury. Methods and results: In this study, we identified the downregulation of m6A demethylase ALKBH5, an m6A “eraser” that is responsible for increased m6A methylation, in the heart after birth. Notably, ALKBH5 knockout mice exhibited decreased cardiac regenerative ability and heart function after neonatal apex resection. Conversely, forced expression of ALKBH5 via adeno-associated virus-9 (AAV9) delivery markedly reduced the infarct size, restored cardiac function and promoted CM proliferation after myocardial infarction in juvenile (7 days old) and adult (8-weeks old) mice. Mechanistically, ALKBH5-mediated m6A demethylation improved the mRNA stability of YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). The modulation of ALKBH5 and YTHDF1 expression in human induced pluripotent stem cell-derived cardiomyocytes consistently yielded similar results. Conclusion: Taken together, our findings highlight the vital role of the ALKBH5-m6A-YTHDF1-YAP axis in the regulation of CMs to re-enter the cell cycle. This finding suggests a novel potential therapeutic strategy for cardiac regeneration.