Loss of m6A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury

再生(生物学) 细胞生物学 心脏病学 生物 医学 化学 内科学
作者
Rui Gong,Xiuxiu Wang,Hanjing Li,Shenzhen Liu,Zuke Jiang,Yiming Zhao,Yang Yu,Zhenbo Han,Ying Yu,Chaorun Dong,Shuainan Li,Binbin Xu,Wenwen Zhang,Ning Wang,Xingda Li,Xinlu Gao,Fan Yang,Djibril Bamba,Wenya Ma,Yu Liu
出处
期刊:Pharmacological Research [Elsevier]
卷期号:174: 105845-105845 被引量:61
标识
DOI:10.1016/j.phrs.2021.105845
摘要

N6-Methyladenosine (m6A), one of the important epigenitic modifications, is very commom in messenger RNAs (mRNAs) of eukaryotes, and has been involved in various diseases. However, the role of m6A modification in heart regeneration after injury remains unclear. The study was conducted to investigate whether targeting methyltransferase-like 3 (METTL3) could replenish the loss of cardiomyocytes (CMs) and improve cardiac function after myocardial infarction (MI). METTL3 knockout mouse line was generated. A series of functional experiments were carried out and the molecular mechanism was further explored. We identified that METTL3, a methyltransferase of m6A methylation, is upregulated in mouse hearts after birth, which is the opposite of the changes in CMs proliferation. Furthermore, both METTL3 heterozygous knockout mice and administration of METTL3 shRNA adenovirus in mice exhibited CMs cell cycle re-entered, infract size decreased and cardiac function improved after MI. Mechanically, the silencing of METTL3 promoted CMs proliferation by reducing primary miR-143 (pri-miR-143) m6A modificaiton, thereby inhibiting the pri-miR-143 into mature miR‐143‐3p. Moreover, we found that miR-143–3p has targeting effects on Yap and Ctnnd1 so as to regulate CMs proliferation. METTL3 deficiency contributes to heart regeneration after MI via METTL3-pri-miR-143-(miR-143)-Yap/Ctnnd1 axis. This study provides new insights into the significance of RNA m6A modification in heart regeneration.
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