ReviewARticlehttps://doi.org/10.1038/s41590-020-0650-41DepartmentofImmunology,WeizmannInstituteofScience,Rehovot,Israel.2DepartmentofMolecularGenetics,WeizmannInstituteofScience,Rehovot,Israel.e-mail:ziv.shulman@weizmann.ac.il;noam.stern-ginossar@weizmann.ac.ilRNAmodificationsarepost-transcriptionalchangestothechemicalcompositionofRNAmoleculesthathavethepoten-tialtoalterRNAfunction.Whileover100differentmodi-fiedbaseshavebeenidentifiedinRNA,themajorityofthesearerestrictedtonon-codingRNAs,especiallytransferRNAandribo-somalRNA.However,severaldistinctmodificationshavebeenreportedtooccurinmammalianmessengerRNAs1.Ofthese,themostprevalentinternallymodifiedbaseisN6-methyladenosine(m6A).m6AwasfirstidentifiedoncellularmRNAsinthe1970s2,3.However,theabsenceofmethodstomapthepreciselocationofm6Aontranscripts,andthelackofinformationaboutthecellularfactorsthatproduceandrecognizem6Aresidues,imposedstronglimita-tionsonthefield.Althoughtheenzymethataddsthem6Amodi-ficationtomRNAswasidentifiedinthelate1990s4,theimmensescientificinterestinRNAmodificationsbeganwiththedevelop-mentofgenome-widem6A-mappingmethods,whichrevealedtheprevalenceofm6Athroughoutthetranscriptome5,6.Sincethen,theroleofm6AinregulatingmRNAfateanditsfunctionalimportanceinvariouscelltypeshavebeenwidelystudied,andm6Aisemergingasawidespreadregulatorymechanismthatcontrolsgeneexpres-sionindiversephysiologicalprocesses.InthisReview,wesummarizerecentstudiesdescribingtheroleofthem6Amodificationinfine-tuningtheimmuneresponse.Wediscussthefunctionsofm6Amodificationinthecontextofinnatesensing,inregulationoftheinnateandadaptiveimmuneresponse,andinimmunesystemdevelopment.Thestudiespresentedhereportraytheimportanceofm6Ainshapingabalancedimmuneresponseandalsoemphasizethepotentialofusingwell-character-izedimmuneregulationpathwaysandthecorrespondinginvivomodelsystemstoshednewlightonm6Aregulatorymechanisms.m6Awritersm6AisaddedtomRNAbyamultisubunit‘writercomplex’com-posedoftheMETTL3–METTL14heterodimerandnumerousadditionaladaptorprotei...
