The Genomic Context and Corecruitment of SP1 Affect ERRα Coactivation by PGC-1α in Muscle Cells

The peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) coordinates the transcriptional network response to promote an improved endurance capacity in skeletal muscle, eg, by coactivating the estrogen-related receptor-alpha (ERR alpha) in the regulation of oxidative substrate metabolism. Despite a close functional relationship, the interaction between these 2 proteins has not been studied on a genomic level. We now mapped the genome-wide binding of ERR alpha to DNA in a skeletal muscle cell line with elevated PGC-1 alpha and linked the DNA recruitment to global PGC-1 alpha target gene regulation. We found that, surprisingly, ERR alpha coactivation by PGC-1 alpha is only observed in the minority of all PGC-1 alpha recruitment sites. Nevertheless, a majority of PGC-1 alpha target gene expression is dependent on ERR alpha. Intriguingly, the interaction between these 2 proteins is controlled by the genomic context of response elements, in particular the relative GC and CpG content, monomeric and dimeric repeat-binding site configuration for ERR alpha, and adjacent recruitment of the transcription factor specificity protein 1. These findings thus not only reveal a novel insight into the regulatory network underlying muscle cell plasticity but also strongly link the genomic context of DNA-response elements to control transcription factor-coregulator interactions.