Mettl3-mediated m6 A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

Fu Qing Jiang, Kun Liu, Jia Xuan Chen, Yan Cao, Wu Yun Chen, Wan Ling Zhao, Guo Hua Song, Chi Qian Liang, Yi Min Zhou, Huan Lei Huang, Rui Jin Huang, Hui Zhao, Kyu Sang Park, Zhenyu Ju, Dongqing Cai, Xu Feng Qi

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Cardiovascular disease is the leading cause of death worldwide due to the inability of adult heart to regenerate after injury. N6-methyladenosine (m6A) methylation catalyzed by the enzyme methyltransferase-like 3 (Mettl3) plays an important role in various physiological and patho-logical bioprocesses. However, the role of m6A in heart regeneration remains largely unclear. To study m6A function in heart regeneration, we modulated Mettl3 expression in vitro and in vivo. Knockdown of Mettl3 significantly increased the proliferation of cardiomyocytes and accelerated heart regeneration following heart injury in neonatal and adult mice. However, Mettl3 overexpres-sion decreased cardiomyocyte proliferation and suppressed heart regeneration in postnatal mice. Conjoint analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq identified Fgf16 as a downstream target of Mettl3-mediated m6A modification during postnatal heart regeneration. RIP-qPCR and luciferase reporter assays revealed that Mettl3 negatively regulates Fgf16 mRNA expression in an m6A-Ythdf2-dependent manner. The silencing of Fgf16 suppressed the proliferation of cardiomyocytes. However, the overexpression of ΔFgf16, in which the m6A consensus sequence was mutated, significantly increased cardiomyocyte proliferation and accelerated heart regeneration in postnatal mice compared with wild-type Fgf16. Our data demonstrate that Mettl3 post-transcriptionally reduces Fgf16 mRNA levels through an m6A-Ythdf2-dependen pathway, thereby controlling cardiomyocyte proliferation and heart regeneration.

Original languageEnglish
Article numbere77014
JournaleLife
Volume11
DOIs
Publication statusPublished - 2022 Nov

Bibliographical note

Publisher Copyright:
© 2022, eLife Sciences Publications Ltd. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint

Dive into the research topics of 'Mettl3-mediated m6 A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration'. Together they form a unique fingerprint.

Cite this