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ERRα rescues histone deacetylation‐mediated down‐regulation of PGC‐1α expression in hypoxia
Author(s) -
Czubryt Michael Paul,
Ramjiawan Angela,
Bagchi Rushita Adhikari
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1097.17
Subject(s) - histone , acetylation , histone deacetylase , hypoxia (environmental) , regulation of gene expression , gene expression , mitochondrial biogenesis , microbiology and biotechnology , chemistry , hdac4 , biology , mitochondrion , biochemistry , gene , organic chemistry , oxygen
PGC‐1α plays a key role in cardiac metabolism by regulating downstream target genes involved in fatty acid oxidation and mitochondrial biogenesis. Our objective was to examine PGC‐1α expression during cardiomyocyte hypoxia. Hypoxia (12h) decreased PGC‐1α expression and promoter histone acetylation. Hypoxia‐induced PGC‐1α down‐regulation was attenuated by a histone deacetylase inhibitor, and was accelerated by an ERRα inverse agonist. We found that ERRα regulates PGC‐1α gene expression via a conserved binding site in the PGC‐1α promoter. Over‐expression of ERRα in isolated cardiomyocytes was sufficient to induce PGC‐1α expression and rescued the loss of PGC‐1α expression during hypoxia. Extending hypoxia to 24h resulted in recovery of PGC‐1α expression, an effect attenuated by an AMP kinase inhibitor or exaggerated by removal of glucose. Hypoxia thus exerts a biphasic effect on PGC‐1α expression: initial down‐regulation due to histone deacetylation, followed by restoration via activation of AMP kinase. While ERRα was not involved in hypoxia‐mediated PGC‐1α down‐regulation, ERRα over‐expression rescued this loss, and ERRα expression was required for basal PGC‐1α expression. Our results describe a novel regulatory mechanism for PGC‐1α expression which may contribute to metabolic derangement during ischemia and heart failure. Supported by the Canadian Institutes of Health Research.