Gene Regulation and Epigenetic Remodeling in Murine Embryonic Stem Cells by c-Myc 英文参考文献.docVIP

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Gene Regulation and Epigenetic Remodeling in Murine Embryonic Stem Cells by c-Myc 英文参考文献.doc

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Gene Regulation and Epigenetic Remodeling in Murine Embryonic Stem Cells by c-Myc 英文参考文献

GeneRegulationandEpigeneticRemodelinginMurine EmbryonicStemCellsbyc-Myc Chin-HsingLin1,ChenWeiLin2,HisashiTanaka3,MatthewL.Fero2,RobertN.Eisenman1* 1DivisionofBasicSciences,FredHutchinsonCancerResearchCenter,Seattle,Washington,UnitedStatesofAmerica,2ClinicalResearchDivision,FredHutchinsonCancer Research Center, Seattle, Washington, United States of America, 3Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America Abstract Background:TheMyconcoprotein,atranscriptionalregulatorinvolvedintheetiologyofmanydifferenttumortypes,has beendemonstratedtoplayanimportantroleinthefunctionsofembryonicstem(ES)cells.Nonetheless,itisstillunclearas towhetherMychasuniquetargetandfunctionsinEScells. Methodology/PrincipalFindings:Toelucidatetheroleofc-MycinmurineEScells,wemappeditsgenomicbindingsitesby chromatin-immunoprecipitationcombinedwithDNAmicroarrays(ChIP-chip).Inadditiontopreviouslyidentifiedtargetswe identified genes involved in pluripotency, early development, and chromatin modification/structure that are bound and regulatedbyc-MycinmurineEScells.MycalsobindsandregulateslocipreviouslyidentifiedasPolycomb(PcG)targets, includinggenesthatcontainbivalentchromatindomains.Todeterminewhetherc-Mycinfluencestheepigeneticstateof Myc-boundgenes,weassessedthepatternsoftrimethylationofhistoneH3-K4andH3-K27inmEScellscontainingnormal, increased,andreducedlevelsofc-Myc.Ouranalysisrevealswidespreadandsurprisinglydiversechangesinrepressiveand activatinghistonemethylationmarksbothproximalanddistaltoMycbindingsites.Furthermore,analysisofbulkchromatin fromphenotypicallynormalc-mycnullE7embryosdemonstratesa70–80%decreaseinH3-K4me3,withlittlechangeinH3- K27me3,comparedtowild-typeembryosindicatingthatMycisrequiredtomaintainnormallevelsofhistonemethylation. Conclusions/Significance:WeshowthatMycinduceswidespreadanddiversechangesinhistonemethylationinEScells. We postulate that these changes are indirect effects of Myc mediated by its regulation of targe