title: Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1α in the regulation of the hypoxic gene program.
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.
authors.affiliation: Focal Area Growth and Development, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Baresic
authors.affiliation: Focal Area Growth and Development, Biozentrum, University of Basel, Basel, Switzerland Focal Area Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland Swiss Institute of Bioinformatics, Basel, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Salatino
authors.affiliation: Focal Area Growth and Development, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kupr
authors.affiliation: Focal Area Computational and Systems Biology, Biozentrum, University of Basel, Basel, Switzerland Swiss Institute of Bioinformatics, Basel, Switzerland erik.vannimwegen@unibas.ch christoph.handschin@unibas.ch.
authors.forename: Erik
authors.initials: E
authors.lastname: van Nimwegen
authors.affiliation: Focal Area Growth and Development, Biozentrum, University of Basel, Basel, Switzerland erik.vannimwegen@unibas.ch christoph.handschin@unibas.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D025341:Principal Component Analysis; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D004268:DNA-Binding Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse