Cohen Todd J, Waddell David S, Barrientos Tomasa, Lu Zhonghua, Feng Guoping, Cox Gregory A, Bodine Sue C, Yao Tso-Pang
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, 27710.
Section of Neurobiology, Physiology & Behavior, University of California, Davis, California 95616.
J Biol Chem. 2007 Nov 16;282(46):33752-33759. doi: 10.1074/jbc.M706268200. Epub 2007 Sep 16.
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.
神经活动积极调节肌肉基因表达。这种调节对于确定肌肉功能和突触蛋白表达至关重要。然而，神经活动如何传递到细胞核并与肌肉转录机制相连接尚不清楚。在此，我们确定组蛋白脱乙酰酶HDAC4是连接神经活动与肌肉转录的关键连接物。我们发现HDAC4通常集中在神经支配肌肉的神经肌肉接头（NMJ）处。值得注意的是，通过手术去神经支配或神经肌肉疾病减少神经输入会使HDAC4从NMJ解离，并显著诱导其表达，导致HDAC4大量积聚在细胞核中。我们提供的证据表明，细胞核中积聚的HDAC4负责去神经支配后突触基因的协同诱导。HDAC4失活可阻止去神经支配诱导的突触乙酰胆碱受体（nAChR）和MUSK转录，而HDAC4的强制表达则模拟去神经支配并激活整个肌纤维中的异位nAChR转录。我们确定HDAC4通过调节Dach2-肌细胞生成素转录级联来执行活性依赖性转录，其中HDAC4对阻遏物Dach2的抑制允许转录因子肌细胞生成素的诱导，进而激活突触基因表达。我们的发现确立了HDAC4作为一种神经活动调节的脱乙酰酶以及将神经活动传递到肌肉转录机制的关键信号成分。
