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.
Cohen
Todd J
TJ
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, 27710.
Waddell
David S
DS
Section of Neurobiology, Physiology & Behavior, University of California, Davis, California 95616.
Barrientos
Tomasa
T
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, 27710.
Lu
Zhonghua
Z
Department of Neurobiology, Duke University, Durham, North Carolina 27710.
Feng
Guoping
G
Department of Neurobiology, Duke University, Durham, North Carolina 27710.
Cox
Gregory A
GA
Jackson Laboratory, Bar Harbor, Maine 04609.
Bodine
Sue C
SC
Section of Neurobiology, Physiology & Behavior, University of California, Davis, California 95616.
Yao
Tso-Pang
TP
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, 27710. Electronic address: yao00001@mc.duke.edu.
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism*; D009469:Neuromuscular Junction; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C485735:Dach2 protein, mouse; D018008:Myogenin; D009687:Nuclear Proteins; D011978:Receptors, Nicotinic; D014157:Transcription Factors; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases