Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany.
DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
Life Sci Alliance. 2019 Apr 9;2(2). doi: 10.26508/lsa.201800233. Print 2019 Apr.
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-position (mA). 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 mA in human and murine-dilated cardiac tissue remains unknown. Transcriptome-wide mapping of mA in mRNA allowed us to catalog mA targets in human and murine hearts. Increased mA methylation was found in human cardiomyopathy. Knockdown and overexpression of the mA 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 mA sites could be a powerful approach to prevent worsening of cardiac function.
概念上类似于 DNA 的修饰，mRNA 经历化学修饰，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腺苷在 N 位的甲基化 (mA)。这使 mRNA 回到了细胞内信息中心枢纽的角色，作为许多生物过程的信息载体、修饰剂和衰减剂。然而，mA 等内部 mRNA 修饰在人和鼠扩张性心脏组织中的精确作用仍然未知。在 mRNA 中转录组范围内对 mA 的映射使我们能够对人和鼠心脏中的 mA 靶标进行编目。在人类扩张型心肌病中发现 mA 甲基化增加。mA 书写酶 Mettl3 的敲低和过表达都在体外和体内影响细胞大小和细胞重塑。我们的数据表明，在应激状态下的心肌细胞中，mRNA 甲基化是高度动态的，mRNA 甲基组的变化通过影响转录本稳定性来调节翻译效率。一旦阐明，对特定 mA 位点的甲基化的操作可能是一种防止心脏功能恶化的有效方法。
