Abstract
Electrical activity arising from motor innervation influences skeletal muscle physiology by controlling the expression of many muscle genes, including those encoding acetylcholine receptor (AChR) subunits. How electrical activity is converted into a transcriptional response remains largely unknown. We show that motor innervation controls chromatin acetylation in skeletal muscle and that histone deacetylase 9 (HDAC9) is a signal-responsive transcriptional repressor which is downregulated upon denervation, with consequent upregulation of chromatin acetylation and AChR expression. Forced expression of Hdac9 in denervated muscle prevents upregulation of activity-dependent genes and chromatin acetylation by linking myocyte enhancer factor 2 (MEF2) and class I HDACs. By contrast, Hdac9-null mice are supersensitive to denervation-induced changes in gene expression and show chromatin hyperacetylation and delayed perinatal downregulation of myogenin, an activator of AChR genes. These findings show a molecular mechanism to account for the control of chromatin acetylation by presynaptic neurons and the activity-dependent regulation of skeletal muscle genes by motor innervation.
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Acknowledgements
We thank E. Chopin for technical assistance in chromatin immunoprecipitation (ChIP) assay; C. Antos for kind and helpful assistance; and A. Ravel-Chapuis, M. Vandromme, K. Ancelin, A. de Kerchove d'Exaerde, Y.-G. Gangloff and A. Sergeant for fruitful discussions and critical reading of the manuscript. This work was supported by the Association Française contre les Myopathies, the Centre National de la Recherche Scientifique, the Ministere de l'Education Nationale, de la Recherche et de la Technologie, and grants from the U.S. National Institutes of Health, the Texas Advanced Technology Program, The Robert A. Welch Foundation and the Donald W. Reynolds Foundation to E.N.O. and R.B.D.
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Supplementary information
Supplementary Fig. 1
HDAC 4, 5 and MITR localization in skeletal muscle. (PDF 215 kb)
Supplementary Fig. 2
Myogenin and AChR α subunit are expressed at the same levels in wild-type and Hdac9−/− mice. (PDF 101 kb)
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Méjat, A., Ramond, F., Bassel-Duby, R. et al. Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression. Nat Neurosci 8, 313–321 (2005). https://doi.org/10.1038/nn1408
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DOI: https://doi.org/10.1038/nn1408
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