The histone H3K9 methyltransferase SUV39H links SIRT1 repression to myocardial infarction

Guang Yang, Xinyu Weng, Yuhao Zhao, Xinjian Zhang, Yuanping Hu, Xin Dai, Peng Liang, Peng Wang, LeiLei Ma, Xiaolei Sun, Lei Hou, Huihui Xu, Mingming Fang, Yuehua Li, Thomas Jenuwein, Yong Xu () and Aijun Sun ()
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Guang Yang: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Xinyu Weng: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Yuhao Zhao: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Xinjian Zhang: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Yuanping Hu: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Xin Dai: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Peng Liang: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Peng Wang: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University
LeiLei Ma: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University
Xiaolei Sun: Institute of Biomedical Sciences, Fudan University
Lei Hou: Institute of Biomedical Sciences, Fudan University
Huihui Xu: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Mingming Fang: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Yuehua Li: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Thomas Jenuwein: Max Planck Institute of Immunobiology and Epigenetics
Yong Xu: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University
Aijun Sun: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Myocardial infarction (MI) dampens heart function and poses a great health risk. The class III deacetylase sirtuin 1 (SIRT1) is known to confer cardioprotection. SIRT1 expression is downregulated in the heart by a number of stress stimuli that collectively drive the pathogenesis of MI, although the underlying mechanism remains largely obscure. Here we show that in primary rat neonatal ventricular myocytes (NRVMs), ischaemic or oxidative stress leads to a rapid upregulation of SUV39H, the mammalian histone H3K9 methyltransferase, paralleling SIRT1 downregulation. Compared to wild-type littermates, SUV39H knockout mice are protected from MI. Likewise, suppression of SUV39H activity with chaetocin attenuates cardiac injury following MI. Mechanistically, SUV39H cooperates with heterochromatin protein 1 gamma (HP1γ) to catalyse H3K9 trimethylation on the SIRT1 promoter and represses SIRT1 transcription. SUV39H augments intracellular ROS levels in a SIRT1-dependent manner. Our data identify a previously unrecognized role for SUV39H linking SIRT1 trans-repression to myocardial infarction.

Date: 2017
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DOI: 10.1038/ncomms14941

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