title: The histone H3K9 methyltransferase SUV39H links SIRT1 repression to myocardial infarction.
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.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.|Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Weng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liang
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: LeiLei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Hou
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.|Department of Nursing, Jiangsu Jiankang Vocational College, Nanjing 210029, china.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.|Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D020868:Gene Silencing / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D002316:Cardiotonic Agents; D006657:Histones; D010879:Piperazines; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C002511:chaetocin; C498700:Suv39h1 protein, mouse; C512117:Suv39h1 protein, rat; D008780:Methyltransferases; D056564:Sirtuin 1; D008239:Lysine