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

被引：150

作者：

Han, Zhenbo ^{[1
,2
]}

Wang, Xiuxiu ^{[1
,2
]}

Xu, Zihang ^{[1
,2
]}

Cao, Yang ^{[1
,2
]}

Gong, Rui ^{[1
,2
]}

Yu, Yang ^{[1
,2
]}

Yu, Ying ^{[1
,2
]}

Guo, Xiaofei ^{[1
,2
]}

Liu, Shenzhen ^{[1
,2
]}

Yu, Meixi ^{[1
,2
]}

Ma, Wenya ^{[1
,2
]}

Zhao, Yiming ^{[1
,2
]}

Xu, Juan ^{[4
]}

Li, Xingda ^{[1
,2
]}

Li, Shuainan ^{[1
,2
]}

Xu, Yan ^{[1
,2
]}

Song, Ruijie ^{[1
,2
]}

Xu, Binbin ^{[1
,2
]}

Yang, Fan ^{[1
,2
]}

Bamba, Djibril ^{[1
,2
]}

Sukhareva, Natalia ^{[1
,2
]}

Lei, Hong ^{[1
,2
]}

Gao, Manqi ^{[1
,2
]}

Zhang, Wenwen ^{[1
,2
]}

Zagidullin, Naufal ^{[5
]}

Zhang, Ying ^{[1
,2
]}

Yang, Baofeng ^{[1
,2
]}

Pan, Zhenwei ^{[1
,2
]}

Cai, Benzhi ^{[1
,2
,3
]}

机构：

[1] Harbin Med Univ, Affiliated Hosp 2, Dept Pharm, Harbin 150086, Peoples R China

[2] Harbin Med Univ, Coll Pharm, Dept Pharmacol, Key Lab Cardiovasc Med Res,Minist Educ, Harbin 150086, Peoples R China

[3] Harbin Med Univ, Dept Clin Pharmacol, Heilongjiang Key Lab Drug Res, Harbin 150086, Peoples R China

[4] Harbin Med Univ, Dept Bioinformat, Harbin 150086, Peoples R China

[5] Bashkir State Med Univ, Dept Internal Dis, Ufa 450008, Russia

来源：

THERANOSTICS | 2021年 / 11卷 / 06期

关键词：

Heart regeneration; cardiomyocyte proliferation; m(6)A; ALKBH5; myocardial infarction; PROMOTES PROLIFERATION; M(6)A; METHYLATION; FAILURE; GROWTH; CELLS;

D O I：

10.7150/thno.47354

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

N-6-methyladenosine (m(6)A) RNA modification, a dynamic and reversible process, is essential for tissue development and pathogenesis. However, the potential involvement of m(6)A in the regulation of cardiomyocyte (CM) proliferation and cardiac regeneration remains unclear. In this study, we aimed to investigate the essential role of m(6)A modification in heart regeneration during postnatal and adult injury. Methods and results: In this study, we identified the downregulation of m(6)A demethylase ALKBH5, an m(6)A "eraser" that is responsible for increased m(6)A 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 m(6)A demethylation improved the mRNA stability of YTH N-6-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-m(6)A-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.

引用

页码：3000 / 3016

页数：17

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