Thecontrolandadaptabilityofvirtuallyallbiologicalprocessesinvolvepostsynthesischemicalmodificationofthreeclassesoffundamentalmacromolecules:DNA,RNAandproteins.Oneofthemostabundantmodifica-tions,methylation,iswidespreadthroughoutallking-domsoflife,andinvolvesanalkylationreactionwherebyamethylgroupreplacesahydrogenatom.Methylationiscatalysedbymethyltransferases(‘writers’),whichuseS-adenosylmethionine(SAM)asthemethyldonor;writerscooperatewithdedicated‘erasers’(demethylases)andmethyl‘readers’.Theimportanceofthevariousmethylationpathwaysishighlightedbythefactthattheirderegulationislinkedtomanydiseases1–5.DNAmethylationoccurspredominantlyatpalin-dromicCpGdinucleotidesthroughtheadditionofamethylgrouptothe5ʹpositionofthecytosinepyrimi-dinering,therebygenerating5-methylcytosine(5mC)(Fig.1a;SupplementaryFig.1).Italsooccurs,albeitmorerarely,innon-CpGsequences.Threeenzymes,DNAmethyltransferase1(DNMT1),DNMT3AandDNMT3B,methylateDNAandmaintaingenomicmethylationpatterns2.InwhathasbeenproposedtobetheinitialstepofactiveDNAdemethylationinmam-mals,theten–eleventranslocation(TET)dioxygen-asesoxidizethe5-methylgroupof5mCtoproduce5-hydroxymethylcytosine(5hmC),5-formylcytosineor5-carboxylcytosine6(SupplementaryFig.1).Morerecently,N6-methyladenosine(m6A)wasalsoidentifiedinmammaliangenomes,althoughitsphysiologicalrolesremainunclear7,8.AmoredetaileddiscussionofDNAmethylationcanbefoundinreF.9.MostoftheknownRNAmodificationsaremethyl-ations(morethan70typesofRNAmethylationhavesofarbeenidentified)buttheirmolecularfunctionsremainlargelyunknown(Fig.1b).Untilrecently,thevastmajor-ityofmodificationshadbeenascribedonlytoribosomalRNAand/ortRNAsowingtotheircellularabundance.PioneeringresearchisnowrevealingthatallRNAspe-ciesaremethylated(forexamples,seereFs10–14),andthatdemethylationatspecificsitesoccurs,atleastinthecaseofm6A(reFs15,16)(Fig.1c;SupplementaryFig.1).MethylationofmRNAisanexcitingandrapidlyexpandingfield,whichisreviewedindetailinreF.17.Proteinmethylationoccursmainlyonthesidechains...
