Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1α in the regulation of the hypoxic gene program

Mol Cell Biol. 2014 Aug;34(16):2996-3012. doi: 10.1128/MCB.01710-13. Epub 2014 Jun 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Cell Hypoxia / genetics
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Mice
  • Muscle Fibers, Skeletal / metabolism*
  • PPAR gamma / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Principal Component Analysis
  • RNA Interference
  • Receptors, Estrogen / metabolism
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • ERRalpha estrogen-related receptor
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Receptors, Estrogen
  • Transcription Factor AP-1
  • Transcription Factors

Associated data

  • GEO/GSE51191