MOLECULARBIOLOGYMCM2promotessymmetricinheritanceofmodifiedhistonesduringDNAreplicationNataliyaPetryk1,2*,MariaDalby3*,AliceWenger1,2,CarolineB.Stromme1†,AnneStrandsby1‡,RobinAndersson3§,AnjaGroth1,2§Duringgenomereplication,parentalhistonesarerecycledtonewlyreplicatedDNAwiththeirposttranslationalmodifications(PTMs).Whethersisterchromatidsinheritmodifiedhistonesevenlyremainsunknown.WemeasuredhistonePTMpartitiontosisterchromatidsinembryonicstemcells.WefoundthatparentalhistonesH3-H4segregatetobothdaughterDNAstrandswithaweakleading-strandbias,skewingpartitionattopologicallyassociatingdomain(TAD)bordersandenhancersproximaltoreplicationinitiationzones.Segregationofparentalhistonestotheleadingstrandincreasedmarkedlyincellswithhistone-bindingmutationsinMCM2,partofthereplicativehelicase,exacerbatinghistonePTMsisterchromatidasymmetry.Thisworkrevealshowhistonesareinheritedtosisterchromatidsandidentifiesamechanismbywhichthereplicationmachineryensuressymmetriccelldivision.Histoneposttranslationalmodifications(PTMs)contributetotheestablishmentandmaintenanceofepigeneticchromatinstatesthatregulatetranscriptionalpro-gramsduringdevelopment(1,2),butthemechanismsthatensuretransmissionofhis-tonePTMpatternstodaughtercellsremainun-clear.Chromatinisdisrupteduponreplicationforkpassage,andnucleosomesarerapidlyre-assembledonnewlysynthesizedDNAthroughrecyclingofevictedparentalhistonesanddenovodepositionofnewhistones(3,4).There-cyclingofmodifiedparentalhistonesisacriticalstepinhistonePTMtransmission(5),andearlystudiessuggestedthatparentalhistonessegre-gaterandomlytobothdaughterDNAstrands(6,7).However,whetherhistonePTMinheri-tanceistrulysymmetricandhowparentalhis-tonesaresegregatedtotheleadingandlaggingstrandsofthereplicationforkremainopenques-tions.Multiplereplicationoriginsareusedtoreplicatelargemetazoanchromosomes,andrep-licationforkdirectionality(RFD)andleading-andlagging-strandreplicationthereforealternatealongchromosomes(8,9).Potentialbiasesinseg-regationofmodifiedparentalhistonesdur...
