The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming.

Neural activity actively regulates muscle gene expression. This regulation is crucial for specifying muscle functionality and synaptic protein expression. How neural activity is relayed into nuclei and connected to the muscle transcriptional machinery, however, is not known. Here we identify the histone deacetylase HDAC4 as the critical linker connecting neural activity to muscle transcription. We found that HDAC4 is normally concentrated at the neuromuscular junction (NMJ), where nerve innervates muscle. Remarkably, reduced neural input by surgical denervation or neuromuscular diseases dissociates HDAC4 from the NMJ and dramatically induces its expression, leading to robust HDAC4 nuclear accumulation. We present evidence that nuclear accumulated HDAC4 is responsible for the coordinated induction of synaptic genes upon denervation. Inactivation of HDAC4 prevents denervation-induced synaptic acetyl-choline receptor (nAChR) and MUSK transcription whereas forced expression of HDAC4 mimics denervation and activates ectopic nAChR transcription throughout myofibers. We determined that HDAC4 executes activity-dependent transcription by regulating the Dach2-myogenin transcriptional cascade where inhibition of the repressor Dach2 by HDAC4 permits the induction of the transcription factor myogenin, which in turn activates synaptic gene expression. Our findings establish HDAC4 as a neural activity-regulated deacetylase and a key signaling component that relays neural activity to the muscle transcriptional machinery.