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1、5RegulationofMuscleGeneExpressionbyHistoneDeacetylasesTimothyA.McKinsey,PhDandEricN.Olson,PhDCONTENTSSUMMARYHISTONEACETYLATIONANDCHROMATINSTRUCTURETRANSCRIPTIONALCONTROLOFSKELETALMUSCLEDIFFERENTIATIONINHIBITIONOFSKELETALMUSCLEDIFFERENTIATIONBYCLASSIIHDAC-MEF2INTERACTIONSINHIB
2、ITIONOFSKELETALMUSCLEDIFFERENTIATIONBYCLASSIHDAC-MYODINTERACTIONSCONVERTINGMYODANDMEF2FROMREPRESSORSTOACTIVATORSOFSKELETALMYOGENESISDIFFERENTIALEFFECTSOFHDACINHIBITORSONSKELETALMUSCLECLASSIIHDACSANDMUSCLEFIBERTYPECLASSIIIHDACSINSKELETALMUSCLEHDACSINTHEHEARTPARADOXICALBLOCKADE
3、OFCARDIACHYPERTROPHYBYHDACINHIBITORSPOTENTIALROLESOFCLASSIIHDACSINHEARTDEVELOPMENTFrom:CancerDrugDiscoveryandDevelopmentHistoneDeacetylases:TranscriptionalRegulationandOtherCellularFunctionsEditedby:E.Verdin©HumanaPressInc.,Totowa,NJ107108McKinseyandOlsonHDACSINSMOOTHMUSCLETH
4、ERAPEUTICIMPLICATIONSINMUSCLEANDBEYONDACKNOWLEDGMENTSREFERENCESSUMMARYHistonedeacetylases(HDACs)repressgeneexpressionbydeacetylat-inglysineresiduesincorehistones,whichpromoteschromatincondensa-tionandtherebylimitsaccessofbasaltranscriptionalmachinerytogeneregulatoryelements.I
5、nthepast5years,HDACshaveemergedaskeyreg-ulatorsofgeneexpressioninmuscle.Inthischapter,wediscusstheinitialfindingslinkingHDACstothecontrolofstriatedmusclecelldifferentia-tionandgrowth.Inaddition,wedescribeworkthatestablishedrolesforasubsetofHDACsassignalintegratorsthatcouplecu
6、esemanatingfromthecellsurfacetomuscle-specificgenesinthenucleus,andwespeculateonthepotentialtomanipulatetheseregulatorycascadeswithsmallmole-culesasameanstotreatcardiacandskeletalmyopathies.KeyWords:Histonedeacetylase,transcription,muscledifferentiation,musclehypertrophy,MEF2
7、,MyoD.HISTONEACETYLATIONANDCHROMATINSTRUCTUREIneukaryotes,histone-dependentpackagingofgenomicDNAintochromatinisacentralmechanismforgeneregulation.Thebasicunitofchromatinisthenucleosome,whichcomprises146bpofDNAwrappedaroundahistoneoctamerthatconsistsoftwocopieseachofhistonesH2
8、A,H2B,H3,andH4.Nucleosomesinteracttocreateahighlycompactstruc-tureth
