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Ischemic Preconditioning Confers Epigenetic Repression of Mtor and Induction of Autophagy Through G9a-Dependent H3K9 Dimethylation

Gidlöf, Olof LU ; Johnstone, Andrea L; Bader, Kerstin; Khomtchouk, Bohdan B; O'Reilly, Jiaqi J; Celik, Selvi LU ; Van Booven, Derek J; Wahlestedt, Claes; Metzler, Bernhard and Erlinge, David LU (2016) In Journal of the American Heart Association 5(12).
Abstract

BACKGROUND: 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.

METHODS AND RESULTS: 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... (More)

BACKGROUND: 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.

METHODS AND RESULTS: 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.

CONCLUSIONS: 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.

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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of the American Heart Association
volume
5
issue
12
publisher
Wiley-Blackwell
external identifiers
  • wos:000390787700014
ISSN
2047-9980
DOI
10.1161/JAHA.116.004076
language
English
LU publication?
yes
id
faee9ba4-97ac-40c0-ae76-0c0be6601522
date added to LUP
2017-06-30 13:40:25
date last changed
2017-09-18 11:37:07
@article{faee9ba4-97ac-40c0-ae76-0c0be6601522,
  abstract     = {<p>BACKGROUND: 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.</p><p>METHODS AND RESULTS: 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.</p><p>CONCLUSIONS: 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.</p>},
  articleno    = {e004076},
  author       = {Gidlöf, Olof and Johnstone, Andrea L and Bader, Kerstin and Khomtchouk, Bohdan B and O'Reilly, Jiaqi J and Celik, Selvi and Van Booven, Derek J and Wahlestedt, Claes and Metzler, Bernhard and Erlinge, David},
  issn         = {2047-9980},
  language     = {eng},
  month        = {12},
  number       = {12},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of the American Heart Association},
  title        = {Ischemic Preconditioning Confers Epigenetic Repression of Mtor and Induction of Autophagy Through G9a-Dependent H3K9 Dimethylation},
  url          = {http://dx.doi.org/10.1161/JAHA.116.004076},
  volume       = {5},
  year         = {2016},
}