RTA Promoter Demethylation and Histone Acetylation Regulation of Murine Gammaherpesvirus 68 Reactivation 英文参考文献.docVIP

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RTA Promoter Demethylation and Histone Acetylation Regulation of Murine Gammaherpesvirus 68 Reactivation 英文参考文献.doc

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RTAPromoterDemethylationandHistoneAcetylation RegulationofMurineGammaherpesvirus68Reactivation ZhangshengYang1,2,HaidongTang1,2,HaiHuang1,2,HongyuDeng1,3 * 1Center for Infection and Immunity and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China, 2Graduate SchooloftheChineseAcademyofSciences,Beijing,China,3SchoolofDentistry,UniversityofCaliforniaLosAngeles,LosAngeles,California,UnitedStatesofAmerica Abstract Gammaherpesviruses have a common biological characteristic, latency and lytic replication. The balance between these two phasesinmurinegammaherpesvirus68(MHV-68)iscontrolledbythereplicationandtranscriptionactivator(RTA)gene.Inthis report, we investigated the effect of DNA demethylation and histone acetylation on MHV-68 replication. We showed that distinctivemethylationpatternswereassociatedwithMHV-68attheRTApromoterduringlatencyorlyticreplication.Treatmentof MHV-68 latently-infected S11E cells with a DNA methyltransferases (DNMTs) inhibitor 5-azacytidine (5-AzaC), only weakly reactivatedMHV-68,despiteresultedindemethylationoftheviralRTApromoter.Incontrast,treatmentwithahistonedeacetylase (HDAC)inhibitortrichostatinA(TSA)stronglyreactivatedMHV-68fromlatency,andthiswasassociatedwithsignificantchangein histoneH3andH4acetylationlevelsattheRTApromoter.WefurthershowedthatHDAC3wasrecruitedtotheRTApromoterand inhibitedRTAtranscriptionduringvirallatency.However,TSAtreatmentcausedrapidremovalofHDAC3andalsoinducedpassive demethylationattheRTApromoter.Invivo,wefoundthattheRTApromoterwashypomethylatedduringlyticinfectioninthe lungandthatmethylationlevelincreasedwithviruslatentinfectioninthespleen.Collectively,ourdatashowedthathistone acetylation,butnotDNAdemethylation,issufficientforeffectivereactivationofMHV-68fromlatencyinS11Ecells. Citation: Yang Z, Tang H, Huang H, Deng H (2009) RTA Promoter Demethylation and Histone Acetylation Regulation of Murine Gammaherpesvirus 68 Reactivation.PLoSONE4(2):e4556.doi:10.137