Nature Genetics36, 738 - 743 (2004)
Published online: 20 June 2004; | doi:10.1038/ng1378
p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci
Cristiano Simone1, 2, 4, Sonia Vanina Forcales1, 4, David A Hill3, Anthony N Imbalzano3, Lucia Latella1
& Pier Lorenzo Puri1, 2
1
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.
2
The Salk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, California 92093, USA.
3
University of Massachusetts Medical School, Department of Cell Biology, Worcester, Massachusetts 01655, USA.
During skeletal myogenesis, genomic reprogramming toward terminal differentiation is achieved by recruiting chromatin-modifying enzymes to muscle-specific loci1,
2. The relative contribution of extracellular signaling cascades in targeting these enzymes to individual genes is unknown. Here we show that the differentiation-activated p38 pathway3,
4,
5 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/ 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-in vitro, and forced activation of p38/ 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.
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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
