Theranostics 2021; 11(6):3000-3016. doi:10.7150/thno.47354

Research Paper

ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1

Zhenbo Han1†, Xiuxiu Wang1†, Zihang Xu1†, Yang Cao1†, Rui Gong1, Yang Yu1, Ying Yu1, Xiaofei Guo1, Shenzhen Liu1, Meixi Yu1, Wenya Ma1, Yiming Zhao1, Juan Xu3, Xingda Li1, Shuainan Li1, Yan Xu1, Ruijie Song1, Binbin Xu1, Fan Yang1, Djibril Bamba1, Natalia Sukhareva1, Hong Lei1, Manqi Gao1, Wenwen Zhang1, Naufal Zagidullin4, Ying Zhang1, Baofeng Yang1, Zhenwei Pan1✉, Benzhi Cai1,2✉

1. Department of Pharmacy at The Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Medicine Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150086, China
2. Department of Clinical Pharmacology (the Heilongjiang Key Laboratory of Drug Research), Harbin Medical University, Harbin 150086, China
3. Department of Bioinformatics, Harbin Medical University, Harbin 150086, China
4. Department of Internal Diseases, Bashkir State Medical University, Ufa 450008, Russia
These authors contributed equally to this study.

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Citation:
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. ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1. Theranostics 2021; 11(6):3000-3016. doi:10.7150/thno.47354. Available from https://www.thno.org/v11p3000.htm

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Abstract

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.

Keywords: Heart regeneration, cardiomyocyte proliferation, m6A, ALKBH5, myocardial infarction