Han Yanchuang, Du Tailai, Guo Siyao, Wang Lu, Dai Gang, Long Tianxin, Xu Ting, Zhuang Xiaodong, Liu Chen, Li Shujuan, Zhang Dihua, Liao Xinxue, Dong Yugang, Lui Kathy O, Tan Xu, Lin Shuibin, Chen Yili, Huang Zhan-Peng
Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou, China.
Front Cardiovasc Med. 2022 Feb 28;9:852775. doi: 10.3389/fcvm.2022.852775. eCollection 2022.
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 mA modification of 18S rRNA at position A, 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 . 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.
在心脏重塑过程中，增强mRNA翻译介导的蛋白质合成是支持心肌细胞肥大的关键步骤之一。甲基转移酶样蛋白5（METTL5）可催化18S rRNA在A位点的mA修饰，已被证明在胚胎干细胞分化和癌细胞生长过程中调节mRNA翻译效率。METTL5是否以及如何调节心脏肥大仍不清楚。在本研究中，我们构建了一个心脏特异性敲除METTL5的小鼠模型METTL5-cKO。METTL5的功能缺失促进压力超负荷诱导的心肌细胞肥大和不良重塑。在原代心肌细胞中，通过功能获得和功能缺失方法进一步证实了METTL5在心肌细胞肥大生长中的调节功能。机制上，METTL5可以调节PRC2复合体核心成分SUZ12的mRNA翻译，并进一步调节心脏肥大过程中的转录组变化。总之，我们的研究可能揭示了一种通过m6A修饰调节心脏肥大的重要翻译调节因子。
