Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex 英文参考文献.docVIP

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Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex 英文参考文献.doc

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Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex 英文参考文献

SleepLossReducestheDNA-BindingofBMAL1,CLOCK, andNPAS2toSpecificClockGenesintheMouse CerebralCortex Vale′rieMongrain1,2*.,FrancescoLaSpada1.,ThomasCurie1,PaulFranken1* 1CenterforIntegrativeGenomics,UniversityofLausanne,Lausanne,Switzerland,2CenterforAdvancedResearchinSleepMedicine,Ho?pitalduSacre′-CoeurdeMontre′al, DepartmentofPsychiatry,Universite′ deMontre′al,Montre′al,Canada Abstract We have previously demonstrated that clock genes contribute to the homeostatic aspect of sleep regulation. Indeed, mutationsinsomeclockgenesmodifythemarkersofsleephomeostasisandanincreaseinhomeostaticsleepdrivealters clockgeneexpressionintheforebrain.Here,weinvestigateapossiblemechanismbywhichsleepdeprivation(SD)could alterclockgeneexpressionbyquantifyingDNA-bindingofthecore-clocktranscriptionfactorsCLOCK,NPAS2,andBMAL1 tothecis-regulatorysequencesoftargetclockgenesinmice.Usingchromatinimmunoprecipitation(ChIP),wefirstshowed that,asreportedfortheliver,DNA-bindingofCLOCKandBMAL1totargetclockgeneschangesinfunctionoftime-of-dayin thecerebralcortex.TissueextractswerecollectedatZT0(lightonset),26,212,and218,andDNAenrichmentofE-boxor E’-boxcontainingsequenceswasmeasuredbyqPCR.CLOCKandBMAL1bindingtoCry1,Dbp,Per1,andPer2dependedon time-of-day,withmaximumvaluesreachedataroundZT6.WethenobservedthatSD,performedbetweenZT0and 26, significantly decreasedDNA-binding of CLOCK andBMAL1to Dbp,consistent withtheobserved decreasein Dbp mRNA levelsafterSD.TheDNA-bindingofNPAS2andBMAL1toPer2wasalsodecreasedbySD,althoughSDisknowntoincrease Per2expressioninthecortex.DNA-bindingtoPer1andCry1wasnotaffectedbySD.Ourresultsshowthatthesleep-wake history can affect the clock molecular machinery directly at the level of chromatin binding thereby altering the cortical expression of Dbp and Per2 and likely other targets. Although the precise dynamics of the relationship between DNA- binding and mRNA expression, especially for Per2, remains elusive, the results also suggest that part of the reported circadi