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ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
- Source :
- Theranostics
- Publication Year :
- 2021
- Publisher :
- Ivyspring International Publisher, 2021.
-
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.
- Subjects :
- 0301 basic medicine
Cardiac function curve
Induced Pluripotent Stem Cells
Myocardial Infarction
Medicine (miscellaneous)
030204 cardiovascular system & hematology
Biology
Methylation
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Animals
Humans
Regeneration
Myocytes, Cardiac
RNA, Messenger
Induced pluripotent stem cell
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Cells, Cultured
Cell Proliferation
Mice, Knockout
Messenger RNA
Regeneration (biology)
AlkB Homolog 5, RNA Demethylase
RNA-Binding Proteins
Heart
m6A
Cell cycle
ALKBH5
Cell biology
Mice, Inbred C57BL
030104 developmental biology
cardiomyocyte proliferation
Knockout mouse
biology.protein
Demethylase
Heart regeneration
Research Paper
Subjects
Details
- ISSN :
- 18387640
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....60c81584344c3abce9d8d831c5cae385