Loss of m6A methyltransferase METTL5 promotes cardiac hypertrophy through translational control of SUZ12

The methyltransferase-like5 (METTL5), which catalyzes m6A in 18S rRNA at position A1832, has been shown to regulate the efficient of mRNA translation in the differentiation of ES cell and the growth of cancer cells. It remains unknown that whether and how METTL5 regulates cardiac hypertrophy. In this study, we generated a mouse model (METTL5-cKO) with cardiac-specific abolishment 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 cardiomyocyte were further confirmed with both gain- and loss-of-function approaches in primary isolated cardiomyocytes. Mechanically, METTL5 was identified to modulate the mRNA translation of SUZ12, a core component of PRC2 complex, and further regulate the transcriptome shift during cardiac hypertrophy. Therefore, our study uncover an important translational regulator of cardiac hypertrophy. heart mRNA profiles of 1-month old Ctrl and Mettl5-KO mice; heart mRNA profiles of 3-month old Ctrl and Mettl5-cKO mice; heart mRNA profiles of Ctrl and Mettl5-cKO mice 4 weeks post-TAC; mRNA profiles of AdGFP and AdMettl5 NRVMs under PE stimulation.