Transcriptional Network Analysis in Muscle Reveals AP-1 as a Partner of PGC-1α in the Regulation of the Hypoxic Gene Program

Skeletal muscle tissue shows an extraordinary cellular plasticity, but the underlying molecular mechanisms are still poorly understood. Here, we use a combination of experimental and computational approaches to unravel the complex transcriptional network of muscle cell plasticity centered on the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha), a regulatory nexus in endurance training adaptation. By integrating data on genome-wide binding of PGC-1 alpha and gene expression upon PGC-1 alpha overexpression with comprehensive computational prediction of transcription factor binding sites (TFBSs), we uncover a hitherto-underestimated number of transcription factor partners involved in mediating PGC-1 alpha action. In particular, principal component analysis of TFBSs at PGC-1 alpha binding regions predicts that, besides the well-known role of the estrogen-related receptor alpha (ERR alpha), the activator protein 1 complex (AP-1) plays a major role in regulating the PGC-1 alpha-controlled gene program of the hypoxia response. Our findings thus reveal the complex transcriptional network of muscle cell plasticity controlled by PGC-1 alpha.