Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression.
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.
Méjat
Alexandre
A
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.
Ramond
Francis
F
Bassel-Duby
Rhonda
R
Khochbin
Saadi
S
Olson
Eric N
EN
Schaeffer
Laurent
L
D000107:Acetylation; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002843:Chromatin / Q000378:metabolism*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D009121:Muscle Denervation / Q000379:methods; D018482:Muscle, Skeletal / Q000294:innervation / Q000502:physiology*; D018006:Myogenic Regulatory Factors; D018008:Myogenin / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology
D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D064326:MEF2 Transcription Factors; C503801:Myog protein, mouse; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D012097:Repressor Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases