title: The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity.
abstract: Histone deacetylase 4 (HDAC4) binds and inhibits activation of the critical muscle transcription factor myocyte enhancer factor-2 (MEF2). However, the physiological significance of the HDAC4-MEF2 complex in skeletal muscle has not been established. Here we show that in skeletal muscle, HDAC4 is a critical modulator of MEF2-dependent structural and contractile gene expression in response to neural activity. We present evidence that loss of neural input leads to concomitant nuclear accumulation of HDAC4 and transcriptional reduction of MEF2-regulated gene expression. Cell-based assays show that HDAC4 represses structural gene expression via direct binding to AT-rich MEF2 response elements. Notably, using both surgical denervation and the neuromuscular disease amyotrophic lateral sclerosis (ALS) model, we found that elevated levels of HDAC4 are required for efficient repression of MEF2-dependent structural gene expression, indicating a link between the pathological induction of HDAC4 and subsequent MEF2 target gene suppression. Supporting this supposition, we show that ectopic expression of HDAC4 in muscle fibers is sufficient to induce muscle damage in mice. Our study identifies HDAC4 as an activity-dependent regulator of MEF2 function and suggests that activation of HDAC4 in response to chronically reduced neural activity suppresses MEF2-dependent gene expression and contributes to progressive muscle dysfunction observed in neuromuscular diseases.
authors.affiliation: Department of Pharmacology and Cancer Biology, Box 3813, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Cohen
authors.forename: Tomasa
authors.initials: T
authors.lastname: Barrientos
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Sean M
authors.initials: SM
authors.lastname: Garvey
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000378:metabolism*; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; C400300:HDAC4 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
references.citation: Ann Neurol. 2006 Jun;59(6):970-5
references.pmid: 16607616
references.citation: J Biol Chem. 2007 Nov 16;282(46):33752-33759
references.pmid: 17873280
references.citation: Arch Neurol. 1967 Jan;16(1):14-24
references.pmid: 6024250
references.citation: Hum Mol Genet. 2004 Jun 1;13(11):1183-92
references.pmid: 15102712
references.citation: J Biol Chem. 2001 Sep 14;276(37):35042-8
references.pmid: 11470791
references.citation: Science. 1998 Jan 9;279(5348):227-30
references.pmid: 9422695
references.citation: Biochem Biophys Res Commun. 2005 Apr 15;329(3):1001-9
references.pmid: 15752755
references.citation: J Biol Chem. 1999 Apr 23;274(17):12095-102
references.pmid: 10207035
references.citation: Nat Neurosci. 2005 Mar;8(3):313-21
references.pmid: 15711539
references.citation: Physiol Genomics. 2006 Mar 13;25(1):60-74
references.pmid: 16380408
references.citation: Nature. 2000 Nov 2;408(6808):106-11
references.pmid: 11081517
references.citation: Mol Cell Biol. 2005 Oct;25(19):8456-64
references.pmid: 16166628
references.citation: Biochim Biophys Acta. 2006 May;1759(5):240-6
references.pmid: 16797743
references.citation: Mol Cell Biol. 2007 Dec;27(23):8143-51
references.pmid: 17875930
references.citation: Hum Mol Genet. 2006 Aug 1;15(15):2348-62
references.pmid: 16801328
references.citation: Development. 2007 Jul;134(13):2511-9
references.pmid: 17537787
references.citation: Nat Protoc. 2006;1(1):179-85
references.pmid: 17406230
references.citation: J Neurochem. 2005 Jun;93(5):1087-98
references.pmid: 15934930
references.citation: Acta Neuropathol. 1976 Apr 26;34(4):321-7
references.pmid: 1274524
references.citation: J Clin Invest. 2007 Sep;117(9):2459-67
references.pmid: 17786239
references.citation: Nucleic Acids Res. 1997 Apr 15;25(8):1618-25
references.pmid: 9092671
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Annu Rev Cell Dev Biol. 1998;14:167-96
references.pmid: 9891782
references.citation: Eur J Biochem. 2001 Feb;268(4):948-57
references.pmid: 11179961
references.citation: EMBO J. 2001 Nov 15;20(22):6414-23
references.pmid: 11707412