m6A-mRNA methylation regulates cardiac gene expression and cellular growth
m6A-mRNA methylation regulates cardiac gene expression and cellular growth
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DOI：
10.26508/lsa.201800233
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发表时间：
2019-04-01
影响因子：
4.4
通讯作者：
Voelkers, Mirko
中科院分区：
文献类型：
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作者：
Kmietczyk, Vivien;Riechert, Eva;Voelkers, Mirko
概念上类似于DNA的修饰，mrna经过化学修饰，这可以影响它们的活性、定位和稳定性。mRNA中最常见的内部修饰是n -6位腺苷的甲基化（m(6)A）。这使得mRNA重新成为细胞内信息的中心枢纽，在许多生物过程中充当信息载体、修饰剂和衰减剂。然而，内部mRNA修饰如m(6)A在人类和小鼠扩张的心脏组织中的确切作用仍不清楚。mRNA中m(6)A的转录组全图谱使我们能够编目人类和小鼠心脏中的m(6)A靶点。在人类心肌病中发现m(6)A甲基化升高。在体外和体内，m(6)A写作酶Mettl3的敲低和过表达都会影响细胞大小和细胞重塑。我们的数据表明，mRNA甲基化在处于应激状态的心肌细胞中是高度动态的，mRNA甲基化组的变化通过影响转录物的稳定性来调节翻译效率。一旦被阐明，操纵特定m(6)A位点的甲基化可能是防止心功能恶化的有力方法。
Conceptually similar to modifications of DNA, mRNAs undergo chemical modifications, which can affect their activity, localization, and stability. The most prevalent internal modification in mRNA is the methylation of adenosine at the N-6-position (m(6)A). This returns mRNA to a role as a central hub of information within the cell, serving as an information carrier, modifier, and attenuator for many biological processes. Still, the precise role of internal mRNA modifications such as m(6)A in human and murine-dilated cardiac tissue remains unknown. Transcriptome-wide mapping of m(6)A in mRNA allowed us to catalog m(6)A targets in human and murine hearts. Increased m(6)A methylation was found in human cardiomyopathy. Knockdown and overexpression of the m(6)A writer enzyme Mettl3 affected cell size and cellular remodeling both in vitro and in vivo. Our data suggest that mRNA methylation is highly dynamic in cardiomyocytes undergoing stress and that changes in the mRNA methylome regulate translational efficiency by affecting transcript stability. Once elucidated, manipulations of methylation of specific m(6)A sites could be a powerful approach to prevent worsening of cardiac function.