Roles of histone deacetylases in epigenetic regulation emerging paradigms from studies with inhibitors 英文参考文献.docVIP

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Roles of histone deacetylases in epigenetic regulation emerging paradigms from studies with inhibitors 英文参考文献.doc

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Roles of histone deacetylases in epigenetic regulation emerging paradigms from studies with inhibitors 英文参考文献

Delcuveetal.ClinicalEpigenetics2012,4:5 /content/4/1/5 REVIEW OpenAccess Rolesofhistonedeacetylasesinepigenetic regulation:emergingparadigmsfromstudies withinhibitors GenevièvePDelcuve,DilshadHKhanandJamesRDavie* Abstract Thezinc-dependentmammalianhistonedeacetylase(HDAC)familycomprises11enzymes,whichhavespecific andcriticalfunctionsindevelopmentandtissuehomeostasis.Mountingevidencepointstoalinkbetween misregulatedHDACactivityandmanyoncologicandnononcologicdiseases.ThusthedevelopmentofHDAC inhibitorsfortherapeutictreatmentgarnersalotofinterestfromacademicresearchersandbiotechnology entrepreneurs.NumerousstudiesofHDACinhibitorspecificitiesandmolecularmechanismsofactionareongoing. Inoneofthesestudies,massspectrometrywasusedtocharacterizetheaffinitiesandselectivitiesofHDAC inhibitorstowardnativeHDACmultiproteincomplexesincellextracts.Suchanovelapproachreproducesinvivo molecularinteractionsmoreaccuratelythanstandardstudiesusingpurifiedproteinsorproteindomainsastargets andcouldbeveryusefulintheisolationofinhibitorswithsuperiorclinicalefficacyanddecreasedtoxicity comparedtotheonespresentlytestedorapproved.HDACinhibitorinduced-transcriptionalreprogramming, believedtocontributelargelytotheirtherapeuticbenefits,isachievedthroughvariousandcomplexmechanisms notfullyunderstood,includinghistonedeacetylation,transcriptionfactororregulator(includingHDAC1) deacetylationfollowedbychromatinremodelingandpositiveornegativeoutcomeregardingtranscription initiation.Althoughonlyaverylowpercentageofprotein-codinggenesareaffectedbytheactionofHDAC inhibitors,about40%ofnoncodingmicroRNAsareupregulatedordownregulated.Moreover,awholenewworld oflongnoncodingRNAsisemerging,revealinganewclassofpotentialtargetsforHDACinhibition.HDAC inhibitorsmightalsoregulatetranscriptionelongationandhavebeenshowntoimpingeonalternativesplicing. Keywords:histonedeacetylase,HDAC,HDACinhibitors,HDACcomplexes,geneexpression,noncodingRNAs, epigenetics Introduction sites on core histones are read by bromodomain mod- Ac