N6-methyladenosine modulates long non-coding RNA in the developing mouse heart

Abstract

Long non-coding RNAs (lncRNAs) were reported to potentially play a regulatory role in the process of myocardial regeneration in the neonatal mouse. N6-methyladenosine (m6A) modification may play a key role in myocardial regeneration in mice and regulates a variety of biological processes through affecting the stability of lncRNAs. However, the map of m6A modification of lncRNAs in mouse cardiac development still remains unknown. We aimed to investigate the differences in the m6A status of lncRNAs during mouse cardiac development and reveal a potential role of m6A modification modulating lncRNAs in cardiac development and myocardial regeneration during cardiac development in mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) of the heart tissue in C57BL/6 J mice at postnatal day 1 (P1), P7 and P28 were performed to produce stagewise cardiac lncRNA m6A-methylomes in a parallel timeframe with the established loss of an intrinsic cardiac regeneration capacity and early postnatal development. There were significant differences in the distribution and abundance of m6A modifications in lncRNAs in the P7 vs P1 mice. In addition, the functional role of m6A in regulating lncRNA levels was established for selected transcripts with METTL3 silencing in neonatal cardiomyocytes in vitro. Based on our MeRIP-qPCR experiment data, both lncGm15328 and lncRNA Zfp597, that were not previously associated with cardiac regeneration, were found to be the most differently methylated at P1-P7. These two lncRNAs sponged several miRNAs which further regulated multiple mRNAs, including some of which have previously been linked with cardiac regeneration ability. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that differential m6A modifications were more enriched in functions and cellular signalling pathways related to cardiomyocyte proliferation. Our data suggested that the m6A modification on lncRNAs may play an important role in the regeneration of myocardium and cardiac development.

Circular RNAs in organ injury: recent development

“…Our previous study has identified that m6A modification on long non-coding RNAs may play a regulatory role during the regeneration and development of mouse myocardium [107]. In particular, recent studies have also identified multiple circRNAs to play a regulatory in heart injuries.…”

Transcriptomic Approaches to Cardiomyocyte–Biomaterial Interactions: A Review

“…108 In recent years, as important regulators in cardiac cells, various noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) have received increasing attention. 109 The m 6 A-modified lncRNAs potentially are crucial to myocardium regeneration and cardiac development, 110 and the nuclear lncRNA NEAT1 is associated with the conserved oxygensensitive feedback in cardiomyocytes by regulating the processing of miRNA while acting on another target involved in cardioprotection. 111 Considering the fact that most ncRNA transcripts are previously unannotated and their functions and interplays are unclear, 112 transcriptomic approaches have great potential in qualifying and quantifying these unknown transcripts in a single detection.…”