Nature Neuroscience8, 313 - 321 (2005)
Published online: 13 February 2005; | doi:10.1038/nn1408
Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression
Alexandre Méjat1, Francis Ramond1, Rhonda Bassel-Duby2, Saadi Khochbin3, Eric N Olson2
& Laurent Schaeffer1
1
Equipe Différenciation Neuromusculaire, Institut Fédératif de Recherche 128, Unité Mixte de Recherche 5161, Centre National de la Recherche Scientifique/Ecole Normale Supérieure, Ecole Normale Supérieure 46, allée d'Italie, 69364 Lyon Cedex 07, France.
2
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.
3
Institut National de la Santé et de la Recherche Médicale U309, Institut Albert Bonniot, 38706 La Tronche Cedex, France.
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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