Abstract
N6-Methyladenosine (m6A) plays important roles in regulating mRNA processing. Despite rapid progress in this field, little is known about the role and mechanism of m6A modification in myocardial development and cardiomyocyte regeneration. Existing studies have shown that the heart tissues of newborn mice have the capability of proliferation and regeneration, but its mechanism, particularly its relation to m6A methylation, remains unknown. Methods. To systematically profile the mRNA m6A modification pattern in the heart tissues of mice at different developmental stages, we jointly performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) of heart tissues of mice, respectively, aged 1 day old, 7 days old, and 28 days old. Results. We identified the linkages and association between differentially expressed mRNA transcripts and hyper or hypomethylated m6A peaks in C57BL/6J mice at different heart developmental stages. Results showed that the amount of m6A peaks and the level of m6A modification were the lowest in the heart of mice at 1 day old. By contrast, heart tissues from 7-day-old mice tended to possess the most m6A peaks and the highest global m6A level. However, the m6A characteristics of myocardial tissue changed little after 7 days old as compared to that of 1 day old. Specifically, we found 1269 downmethylated genes of 1434 methylated genes in 7-day-old mouse heart tissues as compared to those in 1-day-old mice. Hypermethylation of some specific genes may correlate with the heart's strong proliferative and regenerative capability at the first day after birth. In terms of m6A density, the tendency shifted from coding sequences (CDS) to 3′-untranslated regions (3′UTR) and stop codon with the progression of heart development. In addition, some genes demonstrated remarkable changes both in methylation and expression, like kiss1, plekha6, and megf6, which may play important roles in proliferation. Furthermore, signaling pathways highly related to proliferation such as “Wnt signaling pathway,” “ECM-receptor interaction,” and “cardiac chamber formation” were significantly enriched in 1-day-old methylated genes. Conclusions. Our results reveal a pattern that different m6A modifications are distributed in C57BL/6J heart tissue at different developmental stages, which provides new insights into a novel function of m6A methylation of mRNA in myocardial development and regeneration.
Highlights
The adult human heart does not have sufficient ability to renovate the damaged cardiac cardiomyocytes (CMs), which is the critical factor leading to the high mortality of cardiovascular diseases [1]
Male C57BL/6J mice were randomly assigned to three groups according to different ages (P1, P7, and P28)
The enriched m6A antibody immunomagnetic beads and the recovered m6A-containing messenger RNA (mRNA) fragment were used to construct a conventional sequencing library according to the transcriptome library construction process
Summary
The adult human heart does not have sufficient ability to renovate the damaged cardiac cardiomyocytes (CMs), which is the critical factor leading to the high mortality of cardiovascular diseases [1]. The m6A possesses 1-3 modification sites in each particular mRNA that enrich in near stop codons, 3′UTRs, and RRACH sequence of mRNA These studies suggested that m6A modification has a crucial effect on various cellular pathways and processes, including developmental regulation, the cell cycle, fate determination, and the heat-shock stress response by regulating the splicing, expression, stability, and translation efficiency of mRNAs [23, 24]. The effects of m6A modification on embryonic neural stem cells (NSCs) have been demonstrated during early brain development in newborn mice [26] It follows that the function and correlation of m6A modifications in biological physiology and disease progression have become of great interest [25, 26]. In the present study, we conducted an m6A-specific analysis and bioinformatics analysis in mRNAs of mouse hearts at the three stages, including P1, P7, and P28, in an effort to provide clinical and therapeutic insights and reveal the role and mechanism of m6A in myocardial development
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