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Published on: June 3, 2018
Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration
Fu-Qing Jiang1, Kun Liu1, Jia-Xuan Chen1
1Key Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan University, Guangzhou, China.
Insights
Methyltransferase-like 3 (Mettl3) regulates heart regeneration by controlling cardiomyocyte proliferation. Mettl3 knockdown promotes regeneration, while its overexpression inhibits it, impacting cardiac repair mechanisms.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Epigenetics
Background:
- Cardiovascular disease is a leading cause of mortality globally.
- The adult heart's limited regenerative capacity after injury contributes to poor outcomes.
- The role of N6-methyladenosine (m6A) methylation in cardiac repair is not well understood.
Purpose of the Study:
- To investigate the function of m6A methylation, specifically mediated by methyltransferase-like 3 (Mettl3), in heart regeneration.
- To elucidate the molecular mechanisms by which Mettl3 influences cardiomyocyte proliferation and cardiac repair.
Main Methods:
- Modulation of Mettl3 expression in vitro and in vivo (neonatal and adult mice).
- Analysis of cardiomyocyte proliferation and heart regeneration following injury.
- Integrative analysis of methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq.
- Validation using RIP-qPCR and luciferase reporter assays.
Main Results:
- Mettl3 knockdown enhanced cardiomyocyte proliferation and accelerated heart regeneration.
- Mettl3 overexpression suppressed cardiomyocyte proliferation and impaired heart regeneration.
- Fgf16 was identified as a direct downstream target of Mettl3-mediated m6A modification.
- Mettl3 negatively regulated Fgf16 mRNA expression via an m6A-Ythdf2-dependent pathway, impacting cardiomyocyte proliferation.
Conclusions:
- Mettl3 post-transcriptionally controls Fgf16 mRNA levels through m6A modification.
- This Mettl3-Fgf16 axis is a critical regulator of cardiomyocyte proliferation and postnatal heart regeneration.
- Targeting this pathway may offer novel therapeutic strategies for cardiac repair.
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 pathological 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 overexpression 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.
