Frontiers in Cardiovascular Medicine (Feb 2022)

Loss of m6A Methyltransferase METTL5 Promotes Cardiac Hypertrophy Through Epitranscriptomic Control of SUZ12 Expression

  • Yanchuang Han,
  • Yanchuang Han,
  • Tailai Du,
  • Tailai Du,
  • Siyao Guo,
  • Lu Wang,
  • Gang Dai,
  • Tianxin Long,
  • Tianxin Long,
  • Ting Xu,
  • Ting Xu,
  • Xiaodong Zhuang,
  • Xiaodong Zhuang,
  • Chen Liu,
  • Chen Liu,
  • Shujuan Li,
  • Shujuan Li,
  • Dihua Zhang,
  • Xinxue Liao,
  • Xinxue Liao,
  • Yugang Dong,
  • Yugang Dong,
  • Kathy O. Lui,
  • Xu Tan,
  • Shuibin Lin,
  • Yili Chen,
  • Yili Chen,
  • Zhan-Peng Huang,
  • Zhan-Peng Huang

DOI
https://doi.org/10.3389/fcvm.2022.852775
Journal volume & issue
Vol. 9

Abstract

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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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