Abstract
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 γ coactivator 1α (PGC-1α), a regulatory nexus in endurance training adaptation. By integrating data on genome-wide binding of PGC-1α and gene expression upon PGC-1α 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-1α action. In particular, principal component analysis of TFBSs at PGC-1α binding regions predicts that, besides the well-known role of the estrogen-related receptor α (ERRα), the activator protein 1 complex (AP-1) plays a major role in regulating the PGC-1α-controlled gene program of the hypoxia response. Our findings thus reveal the complex transcriptional network of muscle cell plasticity controlled by PGC-1α.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01710-13.
ACKNOWLEDGMENTS
We thank Anastasia Kralli, Svenia Schnyder, Gesa Santos, Kristoffer Svensson, and Markus Beer for reagents, help, and input in the preparation of the manuscript. We are grateful to the [BC]2 Basel Computational Biology Center for providing computational resources.
This project was funded by ERC Consolidator grant 616830-MUSCLE_NET to C.H., the Swiss National Science Foundation (31003A_135397 to E.V.N. and 310030_132900 to C.H.), SystemsX.ch (CellPlasticity, StoNets, and BrainstemX research projects to E.V.N.), the Swiss Society for Research on Muscle Diseases (SSEM), the Neuromuscular Research Association Basel (NeRAB), the Gebert-Rüf Foundation “Rare Diseases” Program, the University of Basel, and the Biozentrum. S.S. was supported by an IPhD fellowship of the SystemsX.ch Swiss Initiative in Systems Biology.
We have no conflict of interest in regard to this paper.