An Alu Element–Associated Hypermethylation Variant of the POMC Gene Is Associated with Childhood Obesity 英文参考文献.docVIP

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An Alu Element–Associated Hypermethylation Variant of the POMC Gene Is Associated with Childhood Obesity 英文参考文献.doc

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An Alu Element–Associated Hypermethylation Variant of the POMC Gene Is Associated with Childhood Obesity 英文参考文献

AnAluElement–AssociatedHypermethylationVariantof thePOMCGeneIsAssociatedwithChildhoodObesity PeterKuehnen1*,MonaMischke1,SusannaWiegand1,ChristineSers2,BernhardHorsthemke3 ,Susanne Lau4,ThomasKeil5,Young-AeLee5,6,AnnetteGrueters1,HeikoKrude1 1Institut fu¨r Experimentelle Pa¨diatrische Endokrinologie, Charite′ - Universita¨tsmedizin Berlin, Berlin, Germany, 2Institut fu¨r Pathologie, Charite′ - Universita¨tsmedizin Berlin, Berlin, Germany, 3Institut fu¨r Humangenetik, Universita¨tsklinikum Essen, Essen, Germany, 4Pediatric Allergology, Experimental and Clinical Research Center, Universita¨tsmedizinBerlin,Berlin,Germany,5Institutfu¨rSozialmedizinundEpidemiologie,Charite′-Universita¨tsmedizinBerlin,Berlin,Germany,6MaxDelbru¨ckCentrum fu¨rmolekulareMedizin(MDC),Berlin-Buch,Germany Abstract Theindividualriskforcommondiseasesnotonlydependsongeneticbutalsoonepigeneticpolymorphisms.Toassessthe roleofepigeneticvariationsintheindividualriskforobesity,wehavedeterminedthemethylationstatusoftwoCpGislands atthePOMClocusinobeseandnormal-weightchildren.WefoundahypermethylationvarianttargetingindividualCpGsat the intron2–exon3 boundary of the POMC gene by bisulphite sequencing that was significantly associated with obesity. POMCexon3hypermethylationinterfereswithbindingofthetranscriptionenhancerP300andreducesexpressionofthe POMCtranscript.Sinceintron2containsAluelementsthatareknowntoinfluencemethylationintheirgenomicvicinity,the exon3methylationvariantseemstoresultfromanAluelement–triggereddefaultstateofmethylationboundarydefinition. Exon3hypermethylationinthePOMClocusrepresentsthefirstidentifiedDNAmethylationvariantthatisassociatedwith theindividualriskforobesity. Citation: Kuehnen P,MischkeM, Wiegand S,Sers C, Horsthemke B, et al. (2012) An Alu Element–Associated HypermethylationVariant ofthe POMC Gene Is AssociatedwithChildhoodObesity.PLoSGenet8(3):e1002543.doi:10.1371/journal.pgen.1002543 Editor:GilesS.H.Yeo,UniversityofCambridge,UnitedKingdom ReceivedMay23,2011;AcceptedDecemb