Dynamic Patterns of N6-Methyladenosine Profiles of Messenger RNA Correlated with the Cardiomyocyte Regenerability during the Early Heart Development in Mice

Author:

Yang Yuhui12ORCID,Shen Siman12,Cai Yin34,Zeng Kejun12,Liu Keyu12,Li Simeng12,Zeng Lanfen12,Chen Linming12,Tang Jing12,Hu Zhe12,Xia Zhengyuan123ORCID,Zhang Liangqing12ORCID

Affiliation:

1. Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

2. Key Laboratory of Organ Functional Injury and Protection and Department of Translational Medicine of Zhanjiang, Zhanjiang, China

3. State Key Laboratory of Pharmaceutical Biotechnology and Department of Medicine, University of Hong Kong, Hong Kong SAR, China

4. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China

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.

Funder

National Natural Science Foundation of China

Publisher

Hindawi Limited

Subject

Cell Biology,Ageing,General Medicine,Biochemistry

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