Generalized disruption of inherited genomic imprints leads to wide-ranging placental defects and dysregulated fetal growth

摘要

Monoallelicexpressionofimprintedgenes,includingonessolelyexpressedintheplacenta,isessentialfornormalplacentaldevelopmentandfetalgrowth.Tobetterunderstandtheroleofplacentalimprintinginplacentaldevelopmentandfetalgrowth,weexaminedconceptusesdevelopingintheabsenceofmaternallyderivedDNA(cytosine-5-)-methyltransferase1o(DNMT1o).AbsenceofDNMT1oresultsinthepartiallossofmethylationatimprinteddifferentiallymethylateddomain(DMD)sequencesintheembryoandtheplacenta.Mid-gestationE9.5DNMT1o-deficientplacentasexhibitedstructuralabnormalitiesofalltissuelayers.AtE17.5,allexaminedplacentashadaberrantplacentalmorphology,mostnotablyinthespongiotrophoblastandlabyrinthlayers.Abnormalitiesincludedanexpandedvolumefractionofspongiotrophoblasttissuewithextensionofthespongiotrophoblastlayerintothelabyrinth.Manymutantplacentasalsodemonstratedmigrationabnormalitiesofglycogencells.Additionally,thevolumefractionofthelabyrinthwasreduced,aswasthesurfaceareaformaternalfetalgasexchange.Despitetheseplacentalmorphologicabnormalities,approximatelyone-halfofDNMT1o-deficientfetusessurvivedtolategestation(E17.5).Furthermore,DNMT1o-deficientplacentassupportedabroadrangeoffetalgrowth.TheabilityofsomeDNMT1o-deficientandmorphologicallyabnormalplacentastosupportfetalgrowthinexcessofwildtypedemonstratestheimportanceofdifferentialmethylationofDMDsandproperimprintingofdiscretegeneclusterstoplacentalmorphogenesisandfetalgrowth./p/div