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p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci

Nature Genetics volume 36, pages 738–743 (2004)Cite this article

Abstract

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 p38α/β 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 p38α-β in vitro, and forced activation of p38α/β 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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Figure 1: Blockade of p38 by SB203580 inhibits the expression of muscle genes by selectively preventing chromatin remodeling at their regulatory regions.
Figure 2: Blockade of p38 by SB203580 selectively prevents SWI-SNF recruitment at regulatory regions of muscle genes.
Figure 3: Forced activation of p38 in myoblasts by ectopic expression of MKK6EE induces myogenin expression by promoting BRG1 recruitment on the Myog promoter.
Figure 4: Inhibition or absence of SWI-SNF enzymatic activity abrogates MKK6EE-induced activation of muscle gene transcription and skeletal myogenesis.

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Acknowledgements

We thank J. Feramisco for continuous support to the project and for providing the microinjection facility; M. Montminy for support to P.L.P. and C.S.; C. Buckmaster for technical assistance in microinjection; J. Feramisco, V. Sartorelli, J.Y.J. Wang and members of the laboratory of P.L.P. for discussions and critical reading of the manuscript; V. Sartorelli for antibodies to acetylated MyoD; E. Knudsen for BRM, BRG1 and BRG1 (K798R) enzymatic-deficient mutant cDNA; J. Han for antibodies to MEF2c; T. Sudo for antibodies to p38α; and R. Evans for SW13 cells. This project was partially supported by MDA (Research Developmental Grant to P.L.P.) and by Compagnia San Paolo di Torino to Dulbecco Telethon Institute. C.S. was supported by a Telethon fellowship and Sbarro Health Research Organization. S.V.F. is supported by a Marie Curie fellowship.

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Author notes

  1. Cristiano Simone and Sonia Vanina Forcales: These authors equally contributed to this work.

Authors and Affiliations

  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

    Cristiano Simone, Sonia Vanina Forcales, Lucia Latella & Pier Lorenzo Puri

  2. The Salk Institute for Biological Studies, Peptide Biology Laboratory, La Jolla, 92093, California, USA

    Cristiano Simone & Pier Lorenzo Puri

  3. Department of Cell Biology, University of Massachusetts Medical School, Worcester, 01655, Massachusetts, USA

    David A Hill & Anthony N Imbalzano

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  1. Cristiano Simone
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  2. Sonia Vanina Forcales
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Correspondence to Pier Lorenzo Puri.

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Supplementary information

Supplementary Fig. 1

Time course of the assembly of myogenic transcriptosome. (PDF 355 kb)

Supplementary Fig. 2

Comparative analysis of chromatin bound factors at Ckm enhancer and coding sequence. (PDF 575 kb)

Supplementary Fig. 3

ChIP from C2C12 myoblasts cultured in GM and stimulated with TNFa (10 ng/ml) for 1 h with or without SB. (PDF 230 kb)

Supplementary Fig. 4

ChIP from 2C12 myoblasts cultured in GM or induced to differentiate (DM) with or without SB. (PDF 263 kb)

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Simone, C., Forcales, S., Hill, D. et al. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Nat Genet 36, 738–743 (2004). https://doi.org/10.1038/ng1378

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