NucleicAcidsResearch,20181doi:10.1093/nar/gky130N6-MethyladenosinemodificationoflincRNA1281iscriticallyrequiredformESCdifferentiationpotentialDandanYang,JingQiao,GuiyingWang,YuanyuanLan,GuopingLi,XudongGuo,JiajieXi,DanYe,SongchengZhu,WenChen,WenwenJia,YeLeng,XiaopingWanandJiuhongKang*ClinicalandTranslationalResearchCenterofShanghaiFirstMaternityandInfantHealthHospital,ShanghaiKeyLaboratoryofSignalingandDiseaseResearch,CollaborativeInnovationCenterforBrainScience,SchoolofLifeSciencesandTechnology,TongjiUniversity,1239SipingRoad,Shanghai200092,ChinaReceivedJune16,2017;RevisedFebruary10,2018;EditorialDecisionFebruary13,2018;AcceptedFebruary13,2018ABSTRACTPreviousstudieshaverevealedthecriticalrolesofN6-methyladenosine(m6A)modificationofmRNAinembryonicstemcells(ESCs),butthebiologicalfunc-tionofm6AinlargeintergenicnoncodingRNA(lin-cRNA)isunknown.Here,weshowedthattheinternalm6Amodificationoflinc1281mediatesacompetingendogenousRNA(ceRNA)modeltoregulatemouseESC(mESC)differentiation.Wedemonstratedthatlossoflinc1281compromisesmESCdifferentiationandthatm6Aishighlyenrichedwithinlinc1281tran-scripts.Linc1281withRRACUm6Asequencemotifs,butnotanm6A-deficientmutant,restoredthepheno-typeinlinc1281-depletedmESCs.Mechanisticanal-ysesrevealedthatlinc1281ensuresmESCidentitybysequesteringpluripotency-relatedlet-7familymi-croRNAs(miRNAs),andthisRNA-RNAinteractionism6Adependent.Collectively,thesefindingselu-cidatedthefunctionalrolesoflinc1281anditsm6AmodificationinmESCsandidentifiedanovelRNAregulatorymechanism,providingabasisforfurtherexplorationofbroadRNAepigeneticregulatorypat-terns.INTRODUCTIONEmbryonicstemcells(ESCs)havetwodefiningfeatures:theabilityofself-renewalandthecapacitytogiverisetomostcelltypes.TheseuniquefeaturesofESCshavemadethemavaluabletoolforclinicaltherapiesandenabledtheinvitrostudyofearlymammaliandevelopment.Multiplegenes,includingtranscriptionfactors,chromatin-remodelingen-zymesandsignalingmolecules,arepreciselycoordinatedtocontrolESCpluripotency(1,2).Inadditiontoprote...
