A systems approach reveals that the myogenesis genome network is regulated by the transcriptional repressor RP58

Dev Cell. 2009 Dec;17(6):836-48. doi: 10.1016/j.devcel.2009.10.011.

Abstract

We created a whole-mount in situ hybridization (WISH) database, termed EMBRYS, containing expression data of 1520 transcription factors and cofactors expressed in E9.5, E10.5, and E11.5 mouse embryos--a highly dynamic stage of skeletal myogenesis. This approach implicated 43 genes in regulation of embryonic myogenesis, including a transcriptional repressor, the zinc-finger protein RP58 (also known as Zfp238). Knockout and knockdown approaches confirmed an essential role for RP58 in skeletal myogenesis. Cell-based high-throughput transfection screening revealed that RP58 is a direct MyoD target. Microarray analysis identified two inhibitors of skeletal myogenesis, Id2 and Id3, as targets for RP58-mediated repression. Consistently, MyoD-dependent activation of the myogenic program is impaired in RP58 null fibroblasts and downregulation of Id2 and Id3 rescues MyoD's ability to promote myogenesis in these cells. Our combined, multi-system approach reveals a MyoD-activated regulatory loop relying on RP58-mediated repression of muscle regulatory factor (MRF) inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • Gene Regulatory Networks*
  • Inhibitor of Differentiation Protein 2 / metabolism
  • Inhibitor of Differentiation Proteins / metabolism
  • Mice
  • Muscle Development*
  • Muscle, Skeletal / embryology*
  • Myogenic Regulatory Factors / genetics
  • Repressor Proteins / metabolism*

Substances

  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Inhibitor of Differentiation Proteins
  • Myogenic Regulatory Factors
  • Repressor Proteins
  • ZNF238 protein, mouse
  • Idb3 protein, mouse