Abstract
Aim: To systematically classify the profile of the RNA m6A modification landscape of neonatal heart regeneration.Materials and Methods: Cardiomyocyte proliferation markers were detected via immunostaining. The expression of m6A modification regulators was detected using quantitative real-time PCR (qPCR) and Western blotting. Genome-wide profiling of methylation-modified transcripts was conducted with methylation-modified RNA immunoprecipitation sequencing (m6A-RIP-seq) and RNA sequencing (RNA-seq). The Gene Expression Omnibus database (GEO) dataset was used to verify the hub genes.Results: METTL3 and the level of m6A modification in total RNA was lower in P7 rat hearts than in P0 ones. In all, 1,637 methylation peaks were differentially expressed using m6A-RIP-seq, with 84 upregulated and 1,553 downregulated. Furthermore, conjoint analyses of m6A-RIP-seq, RNA-seq, and GEO data generated eight potential hub genes with differentially expressed hypermethylated or hypomethylated m6A levels.Conclusion: Our data provided novel information on m6A modification changes between Day 0 and Day 7 cardiomyocytes, which identified that increased METTL3 expression may enhance the proliferative capacity of neonatal cardiomyocytes, providing a theoretical basis for future clinical studies on the direct regulation of m6A in the proliferative capacity of cardiomyocytes.
Highlights
Myocardial infarction, a leading cause of death worldwide, is characterized by a significant loss of cardiomyocytes and massive replacement of fibrotic tissue [1, 2]
To elucidate whether si-Methyltransferase-like 3 (METTL3) could affect the stability of the identified target genes identified by the bioinformatics analyses, we evaluated the respective transcript stability in vivo
The downregulation of METTL3 is most relevant to the lower m6A modification in P7 than in P0, while several changes, such as ALKB homolog 5 (ALKBH5) and Fat-mass and obesity-related proteins (FTO) in tissue and Methyltransferase-like 14 (METTL14), and ALKBH5 in cardiomyocytes, betrayed the change in m6A modification. These results likely indicate that METTL3 is the key regulator of m6A modification in cardiomyocyte proliferation
Summary
Myocardial infarction, a leading cause of death worldwide, is characterized by a significant loss of cardiomyocytes and massive replacement of fibrotic tissue [1, 2]. Bergmann et al demonstrated that adult cardiomyocytes still show limited regeneration, ranging from 0.3 to 1% per year. For adult mammals, including humans, myocardial injury-induced replacement of cardiomyocytes is not sufficient to restore the contractile function of the injured heart. The mammalian mouse heart exhibits excellent regenerative ability in the early neonatal stages (P0-P3), but this is no longer seen after P7 [4]. This difference has prompted interest in finding the key factor relevant to cardiomyocyte proliferation
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