Emmett-2018-Integrative regulation of physiolo.pdfVIP免费

Thepreciseregulationofgeneexpressionisessentialfortheregulationofmammaliandevelopmentandphysio­logytoensurepropergrowth,function,homeostasisandadaptationtochangingconditions.Generegulationisprimarilymediatedbysequence­specifictranscrip­tionfactors,whichlocalizeatcis-regulatoryenhancerelements1–3.Bindingoflineage-determiningtranscriptionfactorsfacilitateschromatinopeningandbindingofsignal-dependenttranscriptionfactors,includingnuclearreceptors4–10.Thisleadstotheintricateassemblyoftranscriptionalcomplexesthatregulategeneexpres­sion,inpartthroughtherecruitmentoftranscriptionco­regulatorsthatfurthermodulatechromatinstructure,includingthroughthereversibleacetylationofhistoneproteinsbyhistoneacetyltransferases(HATs)andhis­tonedeacetylases(HDACs)11,12.HATactivityisanintrinsicpropertyoftranscriptionco­activators,whichpromotegeneexpressionthroughthetransferofanacetylgroupfromacetyl­CoAtotheε­amineofseverallysineresiduesontheamino­terminaltailsofhistones13–16.HDACsantagonizethefunctionsofHATsthroughthedeacetylationofhistonetailsandthusrepressgeneexpression.Numerousstudieshavedemon­stratedthatprecisecontroloftheseopposingenzymaticfunctionsiscrucialfordevelopmentandphysiology17.Themammaliangenomeencodes11HDACiso­formsthatmakeuptheHDACsuperfamily,whichexertbothspecificandsometimesoverlappingfunctionsinthenucleusandcytosol.ThefirstHDACtobeisolatedandcharacterizedwasHDAC1(refs18–21),andthegeneencodingitisthefoundingmemberofthe11highlycon­servedmammaliangenesmakinguptheHDACfam­ily22.ThosesharingthehighestsequencehomologytoHDAC1arereferredtoasclassIHDACs,whichincludeHDAC1,HDAC2,HDAC3andHDAC8.TheclassIIHDACsincludeHDAC4,HDAC5,HDAC6,HDAC7,HDAC9andHDAC10.ClassIandclassIIHDACsallcontainaconserveddeacetylasedomainandrequirezincforenzymaticfunction19,althoughcatalyticactiv­ityhasbeendifficulttodemonstrateforclassIIaHDACs(HDAC4,HDAC5,HDAC7andHDAC9)17,23.Thesin­gleclassIVHDACisHDAC11,whichdemonstratessequenceconservationwithclassIandclassIIHDACswithinthedeacetylasedo...