N6-methyladenosine modulates long non-coding RNA in the developing mouse heart.
N6-methyladenosine modulates long non-coding RNA in the developing mouse heart.
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N6-甲基腺苷调节发育中的小鼠心脏中的长非编码RNA
DOI：
10.1038/s41420-022-01118-x
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发表时间：
2022-07-20
影响因子：
7
通讯作者：
Zhang, Liangqing
中科院分区：
文献类型：
--
作者：
Shen, Siman;Liu, Keyu;Li, Simeng;Rampes, Sanketh;Yang, Yuhui;Huang, Yifeng;Tang, Jing;Xia, Zhengyuan;Ma, Daqing;Zhang, Liangqing
据报道，长的非编码RNA(LncRNAs)在新生小鼠的心肌再生过程中可能起到调节作用。N6-甲基腺苷(M6A)修饰可能在小鼠心肌再生中起关键作用，并通过影响lncRNAs的稳定性来调节多种生物学过程。然而，小鼠心脏发育过程中lncRNAs m6A修饰的图谱仍不清楚。本研究旨在研究小鼠心脏发育过程中LncRNAs M6A状态的差异，揭示M6A修饰调控LncRNAs在小鼠心脏发育和心肌再生中的潜在作用。对出生后第1天(P1)、P7和P28的C57BL/6 J小鼠心脏组织进行甲基化核糖核酸免疫沉淀测序(MERIP-SEQ)和核糖核酸测序(RNASEQ)，在心脏固有再生能力丧失和出生后早期发育的情况下，在平行的时间框架内产生阶段性心脏LncRNAm6A-甲基组。P7和P1小鼠在lncRNAs中m6A修饰的分布和丰度有显著差异。此外，在体外培养的新生心肌细胞中，M6A在调节LncRNA水平中的功能作用被确定为具有METTL3沉默的特定转录本。根据我们的MERIP-qPCR实验数据，之前与心脏再生无关的lncGm15328和lncRNA Zfp597被发现在P1-P7的甲基化差异最大。这两个lncRNAs融合了几个miRNAs，进一步调节了多个mRNAs，其中一些先前被认为与心脏再生能力有关。基因本体论和京都百科全书的基因和基因组分析表明，差异M6A修饰在与心肌细胞增殖相关的功能和细胞信号通路方面更加丰富。我们的数据提示，lncRNAs上的m6A修饰可能在心肌再生和心脏发育中发挥重要作用。M6A在发育中的小鼠心脏中调节长的非编码RNA的潜在机制的图形摘要。
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. The graphical abstract of the potential mechanism of m6A modulates long non-coding RNA in the developing mouse heart.
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