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Vol. 20, Issue 4, 1120-1131, February 15, 2009

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A Histone Deacetylase 4/Myogenin Positive Feedback Loop Coordinates Denervation-dependent Gene Induction and Suppression

Huibin Tang^*, Peter Macpherson^*, Michael Marvin^*, Eric Meadows, William H. Klein, Xiang-Jiao Yang, and Daniel Goldman^*

*Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109; Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada H3A 1A1

Submitted July 23, 2008; Revised December 8, 2008; Accepted December 10, 2008
Monitoring Editor: Paul Forscher

Muscle activity contributes to formation of the neuromuscular junction and affects muscle metabolism and contractile properties through regulated gene expression. However, the mechanisms coordinating these diverse activity-regulated processes remain poorly characterized. Recently, it was reported that histone deacetylase 4 (HDAC4) can mediate denervation-induced myogenin and nicotinic acetylcholine receptor gene expression. Here, we report that HDAC4 is not only necessary for denervation-dependent induction of genes involved in synaptogenesis (nicotinic acetylcholine receptor and muscle-specific receptor tyrosine kinase) but also for denervation-dependent suppression of genes involved in glycolysis (muscle-specific enolase and phosphofructokinase). In addition, HDAC4 differentially regulates genes involved in muscle fiber type specification by inducing myosin heavy chain IIA and suppressing myosin heavy chain IIB. Consistent with these regulated gene profiles, HDAC4 is enriched in fast oxidative fibers of innervated tibialis anterior muscle and HDAC4 knockdown enhances glycolysis in cultured myotubes. HDAC4 mediates gene induction indirectly by suppressing the expression of Dach2 and MITR that function as myogenin gene corepressors. In contrast, HDAC4 is directly recruited to myocyte enhancer factor 2 sites within target promoters to mediate gene suppression. Finally, we discovered an HDAC4/myogenin positive feedback loop that coordinates gene induction and repression underlying muscle phenotypic changes after muscle denervation.

Address correspondence to: Daniel Goldman (neuroman{at}umich.edu).

Abbreviations used: BTX, -bungarotoxin; COX1, cytochrome c oxidase subunit 1; HDAC, histone deacetylase; Mdh2, malate dehydrogenase 2; Mgn, myogenin; MHC, myosin heavy chain; MSE, muscle-specific enolase; MuSK, muscle-specific receptor tyrosine kinase; NaB, sodium butyrate; nAChR, nicotinic acetylcholine receptor -subunit; NMJ, neuromuscular junction; PFK, phosphofructokinase; SDH, succinate dehydrogenase; TA, tibialis anterior; TSA, trichostatin A; TTX, tetrodotoxin.

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