Loss of m(6)A Methyltransferase METTL5 Promotes Cardiac Hypertrophy Through Epitranscriptomic Control of SUZ12 Expression.
Loss of m(6)A Methyltransferase METTL5 Promotes Cardiac Hypertrophy Through Epitranscriptomic Control of SUZ12 Expression.
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m6A 甲基转移酶 METTL5 的缺失通过表转录组控制 SUZ12 表达促进心脏肥大
DOI：
10.3389/fcvm.2022.852775
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发表时间：
2022
影响因子：
3.6
通讯作者：
Huang ZP
中科院分区：
文献类型：
--
作者：
Han Y;Du T;Guo S;Wang L;Dai G;Long T;Xu T;Zhuang X;Liu C;Li S;Zhang D;Liao X;Dong Y;Lui KO;Tan X;Lin S;Chen Y;Huang ZP
mRNA翻译促进蛋白质合成是心脏重塑过程中支持心肌细胞肥大的关键步骤之一。甲基转移酶样5（methyltransferase-like 5，简称L5）催化18 SrRNA A1832位的m6 A修饰，在胚胎干细胞分化和癌细胞生长过程中，它可以调节mRNA翻译的效率。目前尚不清楚胃L5是否以及如何调节心肌肥厚。在这项研究中，我们建立了一种小鼠模型，即CCL 5-cKO，体内心脏特异性消耗CCL 5。胃L5功能丧失促进压力超负荷诱导的心肌细胞肥大和不良重构通过原代心肌细胞的功能获得和功能丧失方法，进一步证实了心肌L5在心肌细胞肥大生长中的调节功能。在机制上，胃L5可以调节PRC 2复合物的核心组分SUZ 12的mRNA翻译，并进一步调节心肌肥厚过程中的转录组移位。总之，我们的研究可能会发现一个重要的翻译调节心肌肥大通过m6 A修饰。
Enhancement of protein synthesis from mRNA translation is one of the key steps supporting cardiomyocyte hypertrophy during cardiac remodeling. The methyltransferase-like5 (METTL5), which catalyzes m6A modification of 18S rRNA at position A1832, has been shown to regulate the efficiency of mRNA translation during the differentiation of ES cells and the growth of cancer cells. It remains unknown whether and how METTL5 regulates cardiac hypertrophy. In this study, we have generated a mouse model, METTL5-cKO, with cardiac-specific depletion of METTL5 in vivo. Loss function of METTL5 promotes pressure overload-induced cardiomyocyte hypertrophy and adverse remodeling. The regulatory function of METTL5 in hypertrophic growth of cardiomyocytes was further confirmed with both gain- and loss-of-function approaches in primary cardiomyocytes. Mechanically, METTL5 can modulate the mRNA translation of SUZ12, a core component of PRC2 complex, and further regulate the transcriptomic shift during cardiac hypertrophy. Altogether, our study may uncover an important translational regulator of cardiac hypertrophy through m6A modification.
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