Mechanism of cardiomyocyte PGC-1α gene regulation by ERRα

Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (PGC-1 alpha) regulates critical genes involved in cardiac mitochondrial biogenesis and fatty acid oxidation, and its loss is associated with impaired metabolism and various cardiac pathologies. Estrogen-related receptor alpha (ERR alpha) targets many of the same genes as PGC-1 alpha, and extensive cross talk exists between these 2 regulators. Here we report the identification of an evolutionarily conserved ERR alpha binding site within the PGC-1 alpha promoter. Using luciferase reporter assays and overexpression, inhibition, or knockdown of ERR alpha, we show that PGC-1 alpha expression is critically dependent upon ERR alpha in primary cardiomyocytes. We demonstrate that short-term hypoxia results in reduced ERR alpha mRNA expression, which precedes a similar loss of PGC-1 alpha mRNA. However, chromatin immunoprecipitation reveals that despite a key role for ERR alpha in regulating PGC-1 alpha in normoxic cardiomyocytes, ERR alpha loss is not responsible for PGC-1 alpha loss in hypoxia. Histone deacetylase 5 (HDAC5) has previously been demonstrated to strongly inhibit expression of PGC-1 alpha, and we show that overexpression of ERR alpha is sufficient to overcome this repressive effect. Our data elucidates the mechanism by which ERR alpha regulates cardiac PGC-1 alpha gene expression, and suggests that ERR alpha may provide a means to normalize PGC-1 alpha expression that could be useful in the development of strategies aimed at improving cardiac metabolism in disease.