Histone Deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression

Abstract : Electrical activity arising from motor innervation influences skeletal muscle physiology by controlling the expression of many muscle genes, including acetylcholine receptor (AChR) subunits genes. 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 down-regulated upon denervation, with consequent up-regulation of chromatin acetylation and AChR expression. Forced expression of HDAC9 in denervated muscle prevents up-regulation of activity-dependent genes and chromatin acetylation by linking MEF2 and class I HDACs. Conversely, HDAC9 null mice are supersensitive to denervation-induced changes in gene expression and display chromatin hyperacetylation, and delayed perinatal downregulation of myogenin, an activator of AChR genes. These findings reveal a molecular mechanism to account for the control of chromatin acetylation by presynaptic neurons and activity-dependent regulation of skeletal muscle genes by motor innervation.