Circulation.2019;139:533–545.DOI:10.1161/CIRCULATIONAHA.118.036146January22,2019533Editorial,seep546BACKGROUND:N6-Methyladenosine(m6A)methylationisthemostprevalentinternalposttranscriptionalmodificationonmammalianmRNA.Theroleofm6AmRNAmethylationintheheartisnotknown.METHODS:Todeterminetheroleofm6Amethylationintheheart,weisolatedprimarycardiomyocytesandperformedm6AimmunoprecipitationfollowedbyRNAsequencing.Wethengeneratedgenetictoolstomodulatem6Alevelsincardiomyocytesbymanipulatingthelevelsofthem6ARNAmethylasemethyltransferase-like3(METTL3)bothincultureandinvivo.Wegeneratedcardiac-restrictedgain-andloss-of-functionmousemodelstoallowassessmentoftheMETTL3-m6Apathwayincardiachomeostasisandfunction.RESULTS:Wemeasuredthelevelofm6AmethylationoncardiomyocytemRNA,andfoundasignificantincreaseinresponsetohypertrophicstimulation,suggestingapotentialroleform6Amethylationinthedevelopmentofcardiomyocytehypertrophy.Analysisofm6Amethylationshowedsignificantenrichmentingenesthatregulatekinasesandintracellularsignalingpathways.InhibitionofMETTL3completelyabrogatedtheabilityofcardiomyocytestoundergohypertrophywhenstimulatedtogrow,whereasincreasedexpressionofthem6ARNAmethylaseMETTL3wassufficienttopromotecardiomyocytehypertrophybothinvitroandinvivo.Finally,cardiac-specificMETTL3knockoutmiceexhibitmorphologicalandfunctionalsignsofheartfailurewithagingandstress,showingthenecessityofRNAmethylationforthemaintenanceofcardiachomeostasis.CONCLUSIONS:OurstudyidentifiedMETTL3-mediatedmethylationofmRNAonN6-adenosinesasadynamicmodificationthatisenhancedinresponsetohypertrophicstimuliandisnecessaryforanormalhypertrophicresponseincardiomyocytes.Enhancedm6ARNAmethylationresultsincompensatedcardiachypertrophy,whereasdiminishedm6Adriveseccentriccardiomyocyteremodelinganddysfunction,highlightingthecriticalimportanceofthisnovelstress-responsemechanismintheheartformaintainingnormalcardiacfunction.©2018TheAuthors.CirculationispublishedonbehalfoftheAmericanHeartAssociation,Inc.,byWoltersKluwerHealth,Inc....
