Gene Reactivation by 5-Aza-2′-Deoxycytidine–Induced Demethylation Requires SRCAP–Mediated H2A.Z Insertion to Establish Nucleosome Depleted Regions 英文参考文献.docVIP

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Gene Reactivation by 5-Aza-2′-Deoxycytidine–Induced Demethylation Requires SRCAP–Mediated H2A.Z Insertion to Establish Nucleosome Depleted Regions 英文参考文献.doc

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Gene Reactivation by 5-Aza-2′-Deoxycytidine–Induced Demethylation Requires SRCAP–Mediated H2A.Z Insertion to Establish Nucleosome Depleted Regions 英文参考文献

GeneReactivationby5-Aza-29-Deoxycytidine–Induced DemethylationRequiresSRCAP–MediatedH2A.Z InsertiontoEstablishNucleosomeDepletedRegions XiaojingYang1,HoutanNoushmehr2,HanHan1,3,ClaudiaAndreu-Vieyra1,GangningLiang1, PeterA.Jones1* 1Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America,2USCEpigenomeCenter,UniversityofSouthernCalifornia,LosAngeles,California,UnitedStatesofAmerica,3DepartmentofPharmacologyandPharmaceutical Sciences,SchoolofPharmacy,UniversityofSouthernCalifornia,LosAngeles,California,UnitedStatesofAmerica Abstract 5-Aza-29-deoxycytidine,approvedbytheFDAforthetreatmentofmyelodysplasticsyndrome(MDS),isincorporatedinto the DNA of dividing cells where it specifically inhibits DNA methylation by forming covalent complexes with the DNA methyltransferases(DNMTs).InanefforttostudythecorrelationsbetweenDNAmethylation,nucleosomeremodeling,and genereactivation,weinvestigatetheintegratedepigeneticeventsthatworkedcoordinatelytoreprogramthemethylated andclosedpromotersbacktopermissivechromatinconfigurationsafter5-Aza-29-deoxycytidinetreatment.TheChIPresults indicatethatH2A.ZisdepositedatpromoterregionsbytheSnf2-relatedCBPactivatorprotein(SRCAP)complexfollowing DNAdemethylation.Accordingtoourgenome-wideexpressionandDNAmethylationprofiles,wefindthatthecomplete re-activationofsilencedgenesrequirestheinsertionofthehistonevariantH2A.Z,whichfacilitatestheacquisitionofregions fullydepletedofnucleosomeasdemonstratedbyNOMe–seq(NucleosomeOccupancyMethylome–sequencing)assay.In contrast, SRCAP–mediated H2A.Z deposition is not required for maintaining theactive status of constitutively expressed genes. By combining Hpa II digestion with NOMe–seq assay, we show that hemimethylated DNA, which is generated followingdrugincorporation,remainsoccupiedbynucleosomes.OurdatahighlightH2A.Zasanovelandessentialfactor involved in 5-Aza-29-deoxycytidine–induced gene reactivation.