title: Ischemic Preconditioning Confers Epigenetic Repression of Mtor and Induction of Autophagy Through G9a-Dependent H3K9 Dimethylation.
abstract: Ischemic preconditioning (IPC) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post-translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning.
  
  
  
  We used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well-studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium. In order to assess which genes were affected by the increase in H3K9me2 levels, we performed ChIP-Seq and transcriptome profiling using microarray. Two hundred thirty-seven genes were both transcriptionally repressed and enriched in H3K9me2 in the area at risk of IPC mice. Of these, Mtor (Mechanistic target of rapamycin) was chosen for mechanistic studies. Knockdown of the major H3K9 methyltransferase G9a resulted in a significant decrease in H3K9me2 levels across Mtor, increased Mtor expression, as well as decreased autophagic activity in response to rapamycin and serum starvation.
  
  
  
  IPC confers an increase of H3K9me2 levels throughout the Mtor gene-a master regulator of cellular metabolism and a key player in the cardioprotective effect of IPC-leading to transcriptional repression via the methyltransferase G9a. The results of this study indicate that G9a has an important role in regulating cardiac autophagy and the cardioprotective effect of IPC.
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden olof.gidlof@med.lu.se.
authors.forename: Olof
authors.initials: O
authors.lastname: Gidlöf
authors.affiliation: The Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Johnstone
authors.affiliation: Department of Internal Medicine III/Cardiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bader
authors.affiliation: The Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Bohdan B
authors.initials: BB
authors.lastname: Khomtchouk
authors.affiliation: The Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Jiaqi J
authors.initials: JJ
authors.lastname: O'Reilly
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Selvi
authors.initials: S
authors.lastname: Celik
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Van Booven
authors.affiliation: The Center for Therapeutic Innovation and Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.affiliation: Department of Internal Medicine III/Cardiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Metzler
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D063185:Epigenetic Repression; D042421:Histone Code / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D008745:Methylation; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: autophagy; epigenetics; ischemia