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

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 t...

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Autores principales: Han, Zhenbo, Wang, Xiuxiu, Xu, Zihang, Cao, Yang, Gong, Rui, Yu, Yang, Yu, Ying, Guo, Xiaofei, Liu, Shenzhen, Yu, Meixi, Ma, Wenya, Zhao, Yiming, Xu, Juan, Li, Xingda, Li, Shuainan, Xu, Yan, Song, Ruijie, Xu, Binbin, Yang, Fan, Bamba, Djibril, Sukhareva, Natalia, Lei, Hong, Gao, Manqi, Zhang, Wenwen, Zagidullin, Naufal, Zhang, Ying, Yang, Baofeng, Pan, Zhenwei, Cai, Benzhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806463/
https://www.ncbi.nlm.nih.gov/pubmed/33456585
http://dx.doi.org/10.7150/thno.47354
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author Han, Zhenbo
Wang, Xiuxiu
Xu, Zihang
Cao, Yang
Gong, Rui
Yu, Yang
Yu, Ying
Guo, Xiaofei
Liu, Shenzhen
Yu, Meixi
Ma, Wenya
Zhao, Yiming
Xu, Juan
Li, Xingda
Li, Shuainan
Xu, Yan
Song, Ruijie
Xu, Binbin
Yang, Fan
Bamba, Djibril
Sukhareva, Natalia
Lei, Hong
Gao, Manqi
Zhang, Wenwen
Zagidullin, Naufal
Zhang, Ying
Yang, Baofeng
Pan, Zhenwei
Cai, Benzhi
author_facet Han, Zhenbo
Wang, Xiuxiu
Xu, Zihang
Cao, Yang
Gong, Rui
Yu, Yang
Yu, Ying
Guo, Xiaofei
Liu, Shenzhen
Yu, Meixi
Ma, Wenya
Zhao, Yiming
Xu, Juan
Li, Xingda
Li, Shuainan
Xu, Yan
Song, Ruijie
Xu, Binbin
Yang, Fan
Bamba, Djibril
Sukhareva, Natalia
Lei, Hong
Gao, Manqi
Zhang, Wenwen
Zagidullin, Naufal
Zhang, Ying
Yang, Baofeng
Pan, Zhenwei
Cai, Benzhi
author_sort Han, Zhenbo
collection PubMed
description 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 m6A “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.
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spelling pubmed-78064632021-01-15 ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1 Han, Zhenbo Wang, Xiuxiu Xu, Zihang Cao, Yang Gong, Rui Yu, Yang Yu, Ying Guo, Xiaofei Liu, Shenzhen Yu, Meixi Ma, Wenya Zhao, Yiming Xu, Juan Li, Xingda Li, Shuainan Xu, Yan Song, Ruijie Xu, Binbin Yang, Fan Bamba, Djibril Sukhareva, Natalia Lei, Hong Gao, Manqi Zhang, Wenwen Zagidullin, Naufal Zhang, Ying Yang, Baofeng Pan, Zhenwei Cai, Benzhi Theranostics Research Paper 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 m6A “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. Ivyspring International Publisher 2021-01-01 /pmc/articles/PMC7806463/ /pubmed/33456585 http://dx.doi.org/10.7150/thno.47354 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Han, Zhenbo
Wang, Xiuxiu
Xu, Zihang
Cao, Yang
Gong, Rui
Yu, Yang
Yu, Ying
Guo, Xiaofei
Liu, Shenzhen
Yu, Meixi
Ma, Wenya
Zhao, Yiming
Xu, Juan
Li, Xingda
Li, Shuainan
Xu, Yan
Song, Ruijie
Xu, Binbin
Yang, Fan
Bamba, Djibril
Sukhareva, Natalia
Lei, Hong
Gao, Manqi
Zhang, Wenwen
Zagidullin, Naufal
Zhang, Ying
Yang, Baofeng
Pan, Zhenwei
Cai, Benzhi
ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
title ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
title_full ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
title_fullStr ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
title_full_unstemmed ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
title_short ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
title_sort alkbh5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mrna of ythdf1
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806463/
https://www.ncbi.nlm.nih.gov/pubmed/33456585
http://dx.doi.org/10.7150/thno.47354
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