DNA甲基化-综述

ThegenomesofeukaryotescarrychemicalmarksthatareaddedtoeitherDNAorchromatinproteins.Thisepigeneticinformationisnotuniform,butisappliedregionally,anditsignalsorpreserveslocalactivitystates,suchasgenetranscriptionorsilencing1.Thesumtotalofallepigeneticinformationistermedthe‘epigenome’.Ifwearetounderstandthebiologicalandbiomedicalsignificanceofepigeneticphenomena,itisobviouslyimportanttomaptheepigenomeinsomedetail.However,unlikethegenome,theepigenomeishighlyvariablebetweencellsandfluctuatesintimeaccordingtoconditionsevenwithinasinglecell.Therearethereforeatleastasmanyepigenomesastherearecelltypes.Despitethischallenge,anumberofprojectshavestartedtoputepigeneticfleshonthebarebonesofthegenome.ThefocusinthisReviewisonstudiesthathavebeguntodescribethelarge-scaledistributionofoneepigeneticmark—DNAmethylation—innormal(thatis,non-cancerous)tissuesandcelltypes.Althoughitisessentiallydescriptive,thisworkhasturnedupsur-prisingfindingsthatcallforare-assessmentofprevail-ingviewsaboutthesignificanceofmethylgroupsongenomicDNA.Ineukaryotesrangingfromplantstohumans,DNAmethylationisfoundexclusivelyatcytosineresidues.Thispost-syntheticmodificationhasimportantroles.Forexample,itisessentialformammalianembryonicdevelopmentasshownbyearlylethalityinmicethatlackDNAmethyltransferases(DNmTs)2,3.Dnmt-nullmicehavereducedDNAmethylationlevels,buttheprecisereasonsfordeathduringdevelopmentareunclear.DefectsinrepressionoftheinactivatedXchromosomeinfemalecellsandintheestablishmentandmaintenanceofallele-specificexpressionofimprintedgeneshavebeenobserved4–6,ashaselevatedexpressionoftransposonRNAinembryos7.Thesefindings,andnumerousotherstudiesoverthepastdecades,haveledtothegeneraliza-tionthatcytosineDNAmethylationfunctionstomain-taintherepressedchromatinstateandthereforestablysilencepromoteractivity8.manystudiesofDNAmethylationinanimalshavebeencarriedoutinmammaliansystems,inwhichgenomicDNAmethylationisfoundthroughoutthegenomewiththeconspicuousexceptionofshortunmethylatedregionscalledCpGislands(CGIs)9,10(FIG.1).Itisimportanttobearinmind,however,thattheglobalDNAmethylationpatternseeninvertebratesisbynomeansubiquitousamongeukaryotes(TABLE1).Severalwell-studiedmodelsystemshavenorecognizableDnmt-likegenesandaredevoidofDNAmethylation(forexample,theyeastSaccharomycescerevisiaeandthenematodewormCaenorhabditiselegans).Infungithathavegenomic5-methylcytosine(m5C),onlyrepetitiveDNAsequencesaremethylated11(FIG.1a).Themostfre-quentpatternininvertebrateanimalsis‘mosaicmethyla-tion’,comprisingdomainsofheavilymethylatedDNAinterspersedwithdomainsthataremethylationfree12,13(FIG.1c).ThehighestlevelsofDNAmethylationamongalleukaryoteshavebeenobservedinplants,withupto50%ofcytosinebeingmethylatedinsomespecies14.Inmaize,forexample,suchhighlevelsseemtobeduetolargenumbersoftransposons,thedegeneraterelicsofwhichdominateintergenicregionsandaretargetedformethylation15,16(FIG.1e).However,otherplants,suchasArabidopsisthaliana,displayamosaicDNAmethylationpatternthatisreminiscentofinvertebrateanimals(FIG.1b).TheWellcomeTrustCentreforCellBiology,TheUniversityofEdinburgh,MichaelSwannBuilding,TheKing’sBuildings,EdinburghEH93JR,UK.CorrespondencetoA.Be-mail:[e-mail]:10.1038/nrg2341Publishedonline8May2008ImprintedgeneAgenethatisexpressedorsilenceddependingonwhichparentcontributedittothezygote.Inamousecell,forexample,thepaternalinsulin-likegrowthfactoralleleisexpressed,butthematernalalleleisnot.Insomecases,imprintingdependsondifferentialDNAmethylationofgeneregulatoryregions.DNAmethylationlandscapes:provocativeinsightsfromepigenomicsMihoM.SuzukiandAdrianBirdAbstract|Thegenomesofmanyanimals,plantsandfungiaretaggedbymethylationofDNAcytosine.Tounderstandthebiologicalsignificanceofthisepigeneticmarkitisessentialtoknowwhereinthegenomeitislocated.NewtechniquesaremakingiteasiertomapDNAmethylationpatternsonalargescaleandtheresultshavealreadyprovidedsurprises.Inparticular,theconventionalviewthatDNAmethylationfunctionspredominantlytoirreversiblysilencetranscriptionisbeingchallenged.Notonlyispromotermethylationoftenhighlydynamicduringdevelopment,butmanyorganismsalsoseemtotargetDNAmethylationspecificallytothebodiesofactivegenes.NATuReRevIewS|genetics volume9|JuNe2008|465REVIEWS©2008NaturePublishingGroupCpGisland(CGI).ADNApatchofapproximately1,000bp,withinwhichthedinucleotideCpGoccursatclosetoitsexpectedfrequency.Thiscontrastswiththemajorityofthevertebrategenome,inwhichCpGisdepleted.DespitetheabundanceofCpGsthatcouldpotentiallybemethylated,CGIsareunmethylatedingermcellsandmostarealsoDNAmethylationfreeinsomaticcells.Inmammals,CGIsareGC-richinbasecomposition(~65%)comparedwiththegenomeasawhole(~40%).DespitesimilaritiesinDNAmethylationlandscapes,thereareimportantdifferencesbetweenDNAmethyla-tioninanimalsandplants.mostsignificantisthepres-enceofnon-CpGmethylationinplantsthatistargetedtotransposableelementsbyamechanismthatdependsuponsmallinterferingRNAs(siRNAs)17–19.Sofar,thereisnoconvincingevidenceforaparallelmechanisminanimals.Theapparentsimilaritiesanddifferencesbetweenepigenomeswithinandbetween