TheSMAD2/3interactomerevealsthatTGFβcontrolsm6AmRNAmethylationinpluripotencyAlessandroBertero#1,†,StephanieBrown#1,PedroMadrigal1,2,AnnaOsnato1,DanielOrtmann1,LoukiaYiangou1,JunedKadiwala1,NinaC.Hubner3,IgorRuizdelosMozos4,ChristophSadee4,An-SofieLenaerts1,ShotaNakanoh1,RodrigoGrandy1,EdwardFarnell5,JernejUle4,HendrikG.Stunnenberg3,SashaMendjan1,‡,andLudovicVallier1,2,*1WellcomeTrust-MRCCambridgeStemCellInstituteAnneMcLarenLaboratoryandDepartmentofSurgery,UniversityofCambridge,UK2WellcomeTrustSangerInstitute,HinxtonUK3DepartmentofMolecularBiology,RadboudUniversityNijmegen,TheNetherlands4FrancisCrickInstituteandDepartmentofMolecularNeuroscience,UniversityCollegeLondon,UK5DepartmentofPathology,UniversityofCambridge,UK#Theseauthorscontributedequallytothiswork.AbstractTheTGFβpathwayplaysanessentialroleinembryonicdevelopment,organhomeostasis,tissuerepair,anddisease1,2.ThisdiversityoftasksisachievedthroughtheintracellulareffectorSMAD2/3,whosecanonicalfunctionistocontrolactivityoftargetgenesbyinteractingwithtranscriptionalregulators3.Nevertheless,acompletedescriptionofthefactorsinteractingwithSMAD2/3inanygivencelltypeisstilllacking.HereweaddressthislimitationbydescribingtheinteractomeofSMAD2/3inhumanpluripotentstemcells(hPSCs).ThisanalysisrevealsthatSMAD2/3isinvolvedinmultiplemolecularprocessesinadditiontoitsroleintranscription.Inparticular,weidentifyafunctionalinteractionwiththeMETTL3-METTL14-WTAPcomplex,whichdepositsN6-methyladenosine(m6A)4.WeuncoverthatSMAD2/3promotesbindingofthem6Amethyltransferasecomplexontoasubsetoftranscriptsinvolvedinearlycellfatedecisions.ThismechanismdestabilizesspecificSMAD2/3transcriptionaltargets,includingthepluripotencyUsersmayview,print,copy,anddownloadtextanddata-minethecontentinsuchdocuments,forthepurposesofacademicresearch,subjectalwaystothefullConditionsofuse:http://www.nature.com/authors/editorial_policies/license.html#terms*CorrespondenceandrequestsformaterialsshouldbeaddressedtoLudovicVallier(lv225@cam.ac.uk).†Currentaddress:D...
