Roles of Coactivators in Hypoxic Induction of the Erythropoietin Gene 英文参考文献.docVIP

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Roles of Coactivators in Hypoxic Induction of the Erythropoietin Gene 英文参考文献.doc

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Roles of Coactivators in Hypoxic Induction of the Erythropoietin Gene 英文参考文献

RolesofCoactivatorsinHypoxicInductionofthe ErythropoietinGene FengWang1,RuixueZhang2,XiaomengWu1,OliverHankinson1* 1DepartmentofPathologyandLaboratoryMedicine,andJonssonComprehensiveCancerCenter,UniversityofCaliforniaLosAngeles,LosAngeles,California,United States of America, 2Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America Abstract Background:Hypoxia-inducibleexpressionoftheerythropoietin(EPO)geneismediatedprincipallybyhypoxia-inducible factor 2a (HIF-2a) in Hep3B cells under physiologic conditions. How/whether p300/CBP and the members of p160 coactivatorfamilypotentiatehypoxicinductionofendogenousEPOandotherHIF-2aandhypoxia-induciblefactor1a(HIF- 1a)targetgenesremainsunclear. Methodology/PrincipalFindings:Wedemonstrate,usingchromatinimmunoprecipitation(ChIP)analysis,thatthehistone acetyltransferase(HAT)coactivatorsp300,SRC-1andSRC-3arerecruitedtothe39enhanceroftheEPOgeneuponhypoxic stimulation,andthateachassociateswiththeenhancerinaperiodicfashion.HypoxiainducedacetylationoftheEPOgene 59promoterathistone4andlysine23ofhistone3.KnockingdownSRC-3,butnotSRC-1orSRC-2,usingshortinterfering RNAs(siRNAs),reducedEPOtranscriptionalactivity.Knockingdownp300resultedindramaticdown-regulationofhypoxic stimulationofEPOgenetranscription,negatedrecruitmentofRNApolymeraseIItothegene’spromoter,andeliminated hypoxia-stimulatedacetylationatthepromoterandrecruitmentsofSRC-1andSRC-3totheenhancer.Theinhibitoryeffects of knocking down p300 and the chromatin remodeling coactivator, Brm/Brg-1, on EPO transcription were additive, suggestingthatp300andBrm/Brg-1actindependently.p300wasalsorequiredforhypoxiainducedtranscriptionofthe HIF-1atargetgene,VEGF,butwasdispensableforinductionoftwootherHIF-1atargetgenes,PGKandLDHA.Knocking down CBP, a homolog of p300, augmented hypoxic induction of VEGF, LDHA and PGK. Different HIF target genes also exhibiteddifferentrequirementsformembersofthep160coac