Dynamic Changes in Ezh2 Gene Occupancy Underlie Its Involvement in Neural Stem Cell Self-Renewal and Differentiation towards Oligodendrocytes 英文参考文献.docVIP

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Dynamic Changes in Ezh2 Gene Occupancy Underlie Its Involvement in Neural Stem Cell Self-Renewal and Differentiation towards Oligodendrocytes 英文参考文献.doc

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Dynamic Changes in Ezh2 Gene Occupancy Underlie Its Involvement in Neural Stem Cell Self-Renewal and Differentiation towards Oligodendrocytes 英文参考文献

DynamicChangesinEzh2GeneOccupancyUnderlieIts InvolvementinNeuralStemCellSelf-Renewaland DifferentiationtowardsOligodendrocytes FalakSher,ErikBoddeke,MartaOlah,SjefCopray* DepartmentofNeuroscience,UniversityMedicalCenterGroningen,UniversityofGroningen,Groningen,TheNetherlands Abstract Background: The polycomb group protein Ezh2 is an epigenetic repressor of transcription originally found to prevent untimely differentiation of pluripotent embryonic stem cells. We previously demonstrated that Ezh2 is also expressed in multipotent neural stemcells (NSCs). Weshowedthat Ezh2expressionis downregulatedduring NSCdifferentiation into astrocytesorneurons.However,highlevelsofEzh2remainedpresentindifferentiatingoligodendrocytesuntilmyelinating. ThisstudyaimedtoelucidatethetargetgenesofEzh2inNSCsandinpremyelinatingoligodendrocytes(pOLs). Methodology/PrincipalFindings:Weperformedchromatinimmunoprecipitationfollowedbyhigh-throughputsequencing to detect the target genes of Ezh2 in NSCs and pOLs. We found 1532 target genes of Ezh2 in NSCs. During NSC differentiation, the occupancy of these genes by Ezh2 was alleviated. However, when the NSCs differentiated into oligodendrocytes,393ofthesegenesremainedtargetsofEzh2.Analysisofthetargetgenesindicatedthattherepressive activityofEzh2inNSCsconcernsgenesinvolvedinstemcellmaintenance,incellcyclecontrolandinpreventingneural differentiation.AmongthegenesinpOLsthatwerestillrepressedbyEzh2weremostprominentlythoseassociatedwith neuronalandastrocyticcommittedcelllineages.SuppressionofEzh2activityinNSCscausedlossofstemcellcharacteristics, blockedtheirproliferationandultimatelyinducedapoptosis.SuppressionofEzh2activityinpOLsresultedinderangement oftheoligodendrocyticphenotype,duetore-expressionofneuronalandastrocyticgenes,andultimatelyinapoptosis. Conclusions/Significance: OurdataindicatethattheepigeneticrepressorEzh2inNSCsiscrucialforproliferativeactivity and maintenance of neural stemness. During differentiation towards oligodendrocytes, Ezh2 r