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J. Biol. Chem., Vol. 282, Issue 46, 33752-33759, November 16, 2007

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The Histone Deacetylase HDAC4 Connects Neural Activity to Muscle Transcriptional Reprogramming^*

Todd J. Cohen, David S. Waddell¹, Tomasa Barrientos¹, Zhonghua Lu^¶, Guoping Feng^¶, Gregory A. Cox^||, Sue C. Bodine, and Tso-Pang Yao²

From the Department of Pharmacology and Cancer Biology and ^¶Department of Neurobiology, Duke University, Durham, North Carolina 27710, the Section of Neurobiology, Physiology & Behavior, University of California, Davis, California 95616, and the ^||Jackson Laboratory, Bar Harbor, Maine 04609

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.

Received for publication, July 30, 2007 , and in revised form, September 7, 2007.

^* This work was supported in part by the Leukemia and Lymphoma Society (to T. P. Y.), National Institutes of Health grants (to G. C. and S. B.), and the ALS Association (to G. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Box 3813, Duke University Medical Center, Durham, North Carolina 27710. Tel.: 919-613-8654; Fax: 919-668-3954; E-mail: yao00001{at}mc.duke.edu.

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