articlesnaturemedicineVOLUME23|NUMBER2|FEBRUARY2017213PWSisclinicallycharacterizedbyneonatalhypotoniaandfailuretothrive,childhood-onsetobesity,intellectualdisabilityandincreasedriskforpsychosisinadults1.Althoughpaternaldeficiencyofthe15q11–q13chromosomalregioniswelldocumentedastheetiologyofPWS,theprecisemolecularbasisunderlyingtheseclinicalfeaturesremainselusive.Paternallyexpressedgeneswithin15q11–q13,includ-ingSNRPN,MAGEL2,NDNandMKRN3,andnoncodingSnoRNAclustersofSNORD115(HBII-52)andSNORD116(HBII-85),arecon-trolledbyaregulatoryelementdefinedasanimprintingcenter(PWS-IC)2.Amongthesegenes,theSnoRNAclusterSNORD116,locatedbetweenSNRPNandUBE3A,playsacriticalpartinPWSetiology,asindicatedbygenomiccopy-numbervariant(CNV)analyses3–6,andthespecificroleofMAGEL2inPWSremainsasubjectofdebateowingtoconflictingfindingsinhumans3,7–9.SNORD116isprocessedfromitshosttranscript,alongnoncodingRNAthatisthoughttoinitiateatthePWS-IC10.HumanSNORD116andmouseSnord116,includinghosttranscripts,arehighlyconservedintheirgenomicorganizationandimprintedexpressionpatterns10–12;yetthemechanismunderlyingtheimprintedexpressionsofSNPRNandSNORD116isstillunclear.DNAmethylationandhistonemodifi-cationarecommonmechanismsthoughttobeimplicatedingenomicimprinting.ThedifferentialmethylationofCpGislandsinthePWS-ICisconsistentwiththepaternalactivationofthegenes,i.e.,theyarefullymethylatedonthematernalchromosomebutunmethylatedonthepaternalchromosome13.However,histonemodificationssuchastheacetylationofhistoneH3lysine4(H3K4)andthemethylationofhistoneH3lysine9(H3K9)alsoexhibitallele-specificpatternsinthePWS-IC14,15.Althoughhistonemodificationisexpectedfortranscriptionalregulation,itsroleintheregulationofimprintedgenesislessclearandhasbeenviewedasaneventsecondaryto,orasasubstitutefor,DNAmethylation.DNAmethylationinhibitorscanactivatetheexpressionofthematernal-originatedSNRPNinvitro16,butthishasnotbeenreportedinvivo.Inaddition,theinactivationofhistoneH3K9methyltransferaseG9ainmouseembryonicstem(ES)cellsinvitrocanin...
