title: p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci.
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.
authors.affiliation: Laboratory of Gene Expression, Dulbecco Telethon Institute at Fondazione A. Cesalpino, Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Rome 00128, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
authors.forename: Sonia Vanina
authors.initials: SV
authors.lastname: Forcales
authors.forename: David A
authors.initials: DA
authors.lastname: Hill
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Imbalzano
authors.forename: Lucia
authors.initials: L
authors.lastname: Latella
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009132:Muscles / Q000166:cytology / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D007093:Imidazoles; D011725:Pyridines; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580