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: 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, Aijun Sun
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 14941 (03 31 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28361889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Histones
• Piperazines
• Reactive Oxygen Species
• Repressor Proteins
• chaetocin
• Suv39h1 protein, mouse
• Suv39h1 protein, rat
• Methyltransferases
• Sirtuin 1
• Lysine

Topics

• Animals
• Animals, Newborn
• Cardiotonic Agents (pharmacology, therapeutic use)
• Gene Silencing (drug effects)
• Histones (metabolism)
• Lysine (metabolism)
• Methyltransferases (antagonists & inhibitors, deficiency, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Infarction (drug therapy, genetics, metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Piperazines (pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Repressor Proteins (antagonists & inhibitors, deficiency, metabolism)
• Sirtuin 1 (genetics, metabolism)
• Transcription, Genetic
• Up-Regulation (drug effects, genetics)