Evidence for Sequential and Increasing Activation of Replication Origins along Replication Timing Gradients in the Human Genome 英文参考文献.docVIP

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Evidence for Sequential and Increasing Activation of Replication Origins along Replication Timing Gradients in the Human Genome 英文参考文献.doc

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Evidence for Sequential and Increasing Activation of Replication Origins along Replication Timing Gradients in the Human Genome 英文参考文献

EvidenceforSequentialandIncreasingActivationof ReplicationOriginsalongReplicationTimingGradients intheHumanGenome GuillaumeGuilbaud1¤a,Aure′lienRappailles1¤b,AntoineBaker2,3,Chun-LongChen4,AlainArneodo2,3, ArachGoldar5,Yvesd’Aubenton-Carafa4,ClaudeThermes4,BenjaminAudit2,3,OlivierHyrien1* 1InstitutdeBiologiedel’EcoleNormaleSupe′rieure(IBENS),CNRSUMR8197,InsermU1024,Paris,France,2Universite′ deLyon,Lyon,France,3LaboratoireJoliotCurieet Laboratoire de Physique, Ecole Normale Supe′rieure de Lyon, CNRS, Lyon, France, 4Centre de Ge′ne′tique Mole′culaire (CNRS UPR3404), Gif-sur-Yvette, France, 5Commissariata` l’EnergieAtomique(CEA),iBiTec-S,Gif-sur-Yvette,France Abstract Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wideanalysisofDNAreplicationkineticsinseveralhumancelltypesthatcontradictsthisview.DNAcombingin HeLacellssortedintofourtemporalcompartmentsofSphaseshowsthatreplicationoriginsarespacedat40kbintervals andfireassmallclusterswhosesynchronyincreasesduringSphaseandthatreplicationforkvelocity(mean0.7kb/min, maximum 2.0kb/min) remains constant and narrowly distributed through S phase. However, multi-scale analysis of a genome-wide replication timing profile shows a broad distribution of replication timing gradients with practically no regionslargerthan100kbreplicatingatlessthan2kb/min.Therefore,HeLacellslacklargeregionsofunidirectionalfork progression.TemporaltransitionregionsarereplicatedbysequentialactivationoforiginsataratethatincreasesduringS phaseandreplicationtiminggradientsaresetbythedelayandthespacingbetweensuccessiveoriginfiringsratherthanby thevelocityofsingleforks.Activationofinternaloriginsinaspecifictemporaltransitionregionisdirectlydemonstratedby DNA combing of the IGH locus in HeLa cells. Analysis of published origin maps in HeLa cells and published replication