ARTICLEMettl3-mediatedm6ARNAmethylationregulatesthefateofbonemarrowmesenchymalstemcellsandosteoporosisYunshuWu1,LiangXie1,MengyuanWang1,QiuchanXiong1,YuchenGuo1,YuLiang2,JingLi1,RuiSheng1,PengDeng1,YuanWang1,RixinZheng1,YizhouJiang3,LingYe1,QianmingChen1,XuedongZhou1,ShuibinLin2&QuanYuan1N6-methyladenosine(m6A)isthemostabundantepigeneticmodificationineukaryoticmRNAsandisessentialformultipleRNAprocessingeventsduringmammaliandevelopmentanddiseasecontrol.Hereweshowthatconditionalknockoutofthem6AmethyltransferaseMettl3inbonemarrowmesenchymalstemcells(MSCs)inducespathologicalfeaturesofosteoporosisinmice.Mettl3loss-of-functionresultsinimpairedboneformation,incompetentosteogenicdifferentiationpotentialandincreasedmarrowadiposity.Moreover,Mettl3overexpressioninMSCsprotectsthemicefromestrogendeficiency-inducedosteoporosis.Mechanistically,weidentifyPTH(parathyroidhormone)/Pth1r(parathyroidhormonereceptor-1)signalingaxisasanimportantdownstreampathwayform6AregulationinMSCs.KnockoutofMettl3reducesthetranslationefficiencyofMSCslineageallocatorPth1r,anddisruptsthePTH-inducedosteogenicandadipogenicresponsesinvivo.Ourresultsdemonstratethepathologicaloutcomesofm6Amis-regulationinMSCsandunveilnovelepitranscriptomicmechanisminskeletalhealthanddiseases.DOI:10.1038/s41467-018-06898-4OPEN1StateKeyLaboratoryofOralDiseases&NationalClinicalResearchCenterforOralDiseases,WestChinaHospitalofStomatology,SichuanUniversity,610041Chengdu,China.2CenterforTranslationalMedicine,TheFirstAffiliatedHospital,SunYat-senUniversity,Guangzhou510080,China.3InstituteforAdvancedStudy,ShenzhenUniversity,Shenzhen518060,China.Theseauthorscontributedequally:YunshuWu,LiangXie.CorrespondenceandrequestsformaterialsshouldbeaddressedtoX.Z.(email:zhouxd@scu.edu.cn)ortoS.L.(email:linshb6@mail.sysu.edu.cn)ortoQ.Y.(email:yuanquan@scu.edu.cn)NATURECOMMUNICATIONS|(2018)9:4772|DOI:10.1038/s41467-018-06898-4|www.nature.com/naturecommunications11234567890():,;Bonemarrowmesenchymalstemcells(MSCs)arethecommonprogenitorsforosteob...
