p38 Pathway Targets SWI-SNF Chromatin-Remodeling Complex to Muscle-Specific Loci

Nat Genet. 2004 Jul;36(7):738-43. doi: 10.1038/ng1378. Epub 2004 Jun 20.

Abstract

During skeletal myogenesis, genomic reprogramming toward terminal differentiation is achieved by recruiting chromatin-modifying enzymes to muscle-specific loci. The relative contribution of extracellular signaling cascades in targeting these enzymes to individual genes is unknown. Here we show that the differentiation-activated p38 pathway targets the SWI-SNF chromatin-remodeling complex to myogenic loci. Upon differentiation, p38 kinases were recruited to the chromatin of muscle-regulatory elements. Blockade of p38 alpha/beta repressed the transcription of muscle genes by preventing recruitment of the SWI-SNF complex at these elements without affecting chromatin binding of muscle-regulatory factors and acetyltransferases. The SWI-SNF subunit BAF60 could be phosphorylated by p38 alpha-beta in vitro, and forced activation of p38 alpha/beta in myoblasts by expression of a constitutively active MKK6 (refs. 5,6,7) promoted unscheduled SWI-SNF recruitment to the myogenin promoter. Conversely, inactivation of SWI-SNF enzymatic subunits abrogated MKK6-dependent induction of muscle gene expression. These results identify an unexpected function of differentiation-activated p38 in converting external cues into chromatin modifications at discrete loci, by selectively targeting SWI-SNF to muscle-regulatory elements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromatin / metabolism*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Imidazoles / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Muscles / cytology
  • Muscles / metabolism*
  • Pyridines / pharmacology
  • Transcription Factors / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Imidazoles
  • Pyridines
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580