Rui Gong1, Xiuxiu Wang1, Hanjing Li1, Shenzhen Liu1, Zuke Jiang1, Yiming Zhao1, Yang Yu2, Zhenbo Han1, Ying Yu1, Chaorun Dong1, Shuainan Li1, Binbin Xu1, Wenwen Zhang1, Ning Wang1, Xingda Li1, Xinlu Gao1, Fan Yang1, Djibril Bamba1, Wenya Ma1, Yu Liu3, Benzhi Cai4. 1. Department of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (the Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, Harbin 150086, China. 2. Institute of Clinical Pharmacy, the Heilongjiang Key Laboratory of Drug Research, Harbin Medical University, Harbin 150086, China. 3. Department of Clinical Laboratory, The Fourth Hospital, Harbin Medical University, Harbin 150001, China. Electronic address: liuy.doctor@gmail.com. 4. Department of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (the Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), Harbin Medical University, Harbin 150086, China; Institute of Clinical Pharmacy, the Heilongjiang Key Laboratory of Drug Research, Harbin Medical University, Harbin 150086, China. Electronic address: caibz@ems.hrbmu.edu.cn.
Abstract
AIMS: 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). METHODS AND RESULTS: 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. CONCLUSION: 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.
AIMS: 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). METHODS AND RESULTS: 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. CONCLUSION: 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.