Genetic Imprinting and X Inactivation | Learn Science at Scitable

How do these processes work, and why do they often produce similar results? ... For example, if a paternally imprinted gene is inherited by a female, ... Thispagehasbeenarchivedandisnolongerupdated   GeneticImprintingandXInactivation By: TheresaPhillips,Ph.D. (WriteScienceRight) & IngridLobo,Ph.D. (WriteScienceRight) © 2008 NatureEducation  Citation: Phillips, T. & Lobo, I. (2008) GeneticImprintingandXInactivation. NatureEducation 1(1):117 Xinactivationturnsoffentirechromosomes,whereasimprintingturnsoffonlyspecificgenes.Howdotheseprocesseswork,andwhydotheyoftenproducesimilarresults? Aa Aa Aa   Inthemajorityof cases,twocopiesofeachchromosome—andtherefore,twocopiesofeach gene—arriveineveryfertilizedegg.However,insomecases,oneofthegenes withinapairissomehowswitched"off";thisoccursbecauseoftheprocess knownasimprinting.Whetherornotparticulargenesareinactivatedinthis waydependsonwhichparentthegeneswereinheritedfrom.Insuchcases,a geneisonlyexpressedwhenitcomesfromthedesignatedor"correct"parent;thus, ifapersonreceivesthisparticulargenefromhisorherotherparent,the geneispermanentlyturnedoff.Anotherwayinwhichonegenecopycanbe turnedoffisbyinactivationoftheentireXchromosome.Althoughthey sometimesyieldsimilarresults,imprintingandXinactivationareregulatedby completelydifferentmechanisms. DiscoveryofImprinting Genomicimprinting,alsoreferredtoasgameticorparentalimprinting,wasdiscoveredalmostsimultaneouslybytwolaboratoriesin1984.PriortothepublicationsofMcGrathandSolter(1984)andSuranietal.(1984),conflictingresultsexistedaboutwhetherbothparentalgenomeswererequiredfornormaldevelopment.Mostlaboratorieswereunabletogenerateviableembryosfromactivatedoocytes.Thislackofsuccessfulparthenogenesiswassupportiveoftherequirementofbothparentalgenomes,butdirectevidenceofthisrequirementfirstcamefromSuranietal.(1984). Workingwithmice,Suraniandcolleaguesperformedanexperimentattheearlieststagesofdevelopment.Becauseactivatedoocytesdidnotsurviveintodevelopment,theseresearchershypothesizedthatnormaldevelopmentrequiredbothamaternalandapaternalgenome.Totestthisidea,thescientistsreliedontheirabilitytoindependentlymanipulatethematernalandpaternalgenomesthroughthepronucleiofspermandeggcells.Thus,theywereabletocollectnucleifromoocytesandnucleifromspermcellsandmanuallyinjectthesenucleiintoregularoocytes.Suranietal.usedthistechniquetolookatseveraltypesofembryos.Specifically,theteamfirstexaminedembryoscreatedfromeggstowhichthenucleusfromanotheroocytehadbeenadded(thuscreatingacaseofmaternaluniparentaldisomy).Next,theteamconsideredembryoscreatedfromeggstowhichthenucleusofaspermcellhadbeenadded. Uponexaminingtheirresults,Suranietal.notedthatactivatedoocytesalonewerenotviable;similarly,addingthenucleusfromaneggtoaregularoocytedidnotproduceahealthyembryo.Theparthenogenic,activatedoocyteswererescuedonlywhenthescientistsaddedthepaternalcontribution(Table1).Althoughtherescueratewasnot100%(only9of24pregnanciesresultedinlivemousepups),thelevelofsuccesswasstilldramaticconsideringthatnoneoftheembryossurvivedwhentheentiregeneticcontributioncamefromthemother.Theseresultssupportedtheideathatbothmaternalandpaternalcontributionsarerequiredfornormaldevelopment. GeneticComponent NumberofTotalPregnancies NumberofViableEmbryos Activatedoocyte+eggpronucleus 48 0 Activatedoocyte+spermpronucleus 24 9 Table1:Summaryofresultsfromexperimentsexaminingthedifferentialroleofeggorspermpronucleiinmousedevelopment Butwhyarebothtypesofcontributionsrequired,andhowdoesafertilizedeggdifferentiatebetweenthetwo?Suranietal.speculatedthatduringproductionofeggsorsperm,someofthecells'genesareimprintedwithanindicationofthegameteinwhichthegenesbegan.Itwasnotuntil1991,however,thatthissuspicionwasconfirmedviatheidentificationofthefirstpaternallyimprinted(IgfII)andmaternallyimprinted(Igfr2,H19)genes(DeChiaraetal.,1991;Barlowetal.,1991;Bartolomeietal.,1991).Allthreeofthesegenesplayacriticalroleinembryonicdevelopment(Barlow,1995). ImprintinginSomaticCells ImprintingresultsinexpressionpatternsthataredifferentfromclassicalMendelianinheritancepatterns,becauseeventhoughbothparentscontributeequallytothegeneticcontentoftheiroffspring,theimprintedgenescontributedfromthefatherandmotherarenotequallyexpressed.Inparticular,whenthegeneatamaternallyimprintedlocusisexpressed,thecopyoftheimprintedgenefromthemotherisalwaysturned"off,"whereasthecopyfromthefatherisalwaysturned"on."Theoppositeistrueofapaternallyimprintedgene. Sohow,then,areimprintedgenesmarkedtodistinguishbetweenthematernalandpaternalcontributions?Itturnsoutthatsomegeneshavestretchesofalternatingcytosineandguaninenucleotides,whichareknownasCpGislands.Thesesequencesaredomainsthatcanbemethylated.MethylationisatypeofchemicalmodificationofDNAthatcanbecopiedimmediatelyafterreplication,makingitepigeneticallyinherited.Withpropersignals,DNAmethylationcanbesubsequentlyremovedwithoutchangingtheoriginalDNAsequence.Thus,imprintedgenescanbemarkedbyparental-specificmethylationofCpG-richdomains.Afterthatmarkingispresent,theDNAiscompactedviabindingofspecificproteinsthatrecognizethe5-methylcytosines.Animprintcanbeerasedandthenreestablishedduringgametogenesistomatchthesexofthegamete-producingparent,thusplayinganimportantroleinmaintenanceofallele-specificgeneexpression(Arieletal.,1995).Denovomethylationestablishesthesepatternsfordifferenttissues,whicharethenmaintainedduringsomaticcelldivisions. Inmammals,mostimprintedgenesarefoundinclustersonthegenome,andtheseclustersoftencontainthesequencesfornoncodingRNAs.TherelationshipbetweentheexpressionofnoncodingRNAsandthesilencingoflinkedprotein-codinggeneswasstudiedbySleutelsetal.(2002),whousedexpressionofatruncatedAirRNAonmousechromosome7tostudyitsinvolvementinsilencingoftheIGf2r/Slc22a2/Slc22a3genecluster,whichisimprintedandmaternallyexpressed.TheirresultsprovidedevidencethatnoncodingRNAsarealsoanimportantfactoringenomicimprinting. Forimprintingtowork,theepigeneticsignalmustbeconsistentinthematuregameteandthecellsoriginatingfromthezygotethatthisgameteforms;however,thissignalalsohastobereversibleinthenextgeneration,dependingonthesexoftheoffspring.Duringembryonicdevelopment,somaticcellsmaintainmonoallelicexpressionofimprintedgenes,butgermcellsneedtobeimprintedtoreflectthesexoftheembryo.Forexample,ifapaternallyimprintedgeneisinheritedbyafemale,whensheproduceseggs,thepaternalimprintsmustbeerasedandreplacedwiththematernalversion. XInactivation XistandXinactivationXistRNAencompassestheXfromwhichitistranscribed.RNA-fluorescenceinsituhybridizationdetectingXistRNA(red)localizedontheinactiveXinapreparationofcondensedchromosomesfromdifferentiatedmousecells.DNAiscounterstained(blue).CourtesyofDr.AntonWutz.Allrightsreserved.AlthoughbothimprintingandinactivationoftheXchromosomeleadtomonoallelicexpression,thetwoprocessesare,infact,quitedifferent.Specifically,femalemammalsinitiallyhavetwoXchromosomes,butthemajorityofthegenesononeofthemarequicklyturnedoffduringearlyembryonicdevelopment.ThesilencedchromosomethenformsadenselycompactedstructurecalledaBarrbody.(Thisprocessdoesnothappeninmalecells,whichonlyhaveoneXchromosome.)AsoriginallyproposedbyElizabethLyon,theselectionofwhichXchromosomeisinactivatedisrandom,butafterinactivationtakesplace,allthedescendentsofthatcellareinactivatedinthesamewaywithrespecttotheirXchromosomes.Interestingly,certaingenesontheXchromosomethatarealsofoundontheYchromosomeinmalescontinuetobeexpressedevenfromtheBarrbody,althoughhowthatoccursisnotfullyunderstood. Arieletal.(1995)usedpolymerasechainreactiontostudytheextentofmethylationonthenoncodingRNAgenecalledXistinearlymiceembryosandreportedthatmethylationofthatgenewasanimportantpartoftheX-imprintingprocess.Inplacentalmammals,noncodingRNAisalsobelievedtoplayaroleinrandomimprintingoftheXchromosome(Ngetal.,2007).TheXistgene,foundontheXchromosomeitself,producesnoncodingRNA(siRNA)thatassociateswiththeXchromosome,coatingitsentirelength(Figure1).Inadults,theXistgeneisexpressedonlyontheinactiveXchromosome(Xi).ItalsoappearsthattheRNAmightdirectDNAmethylationtothesilentX,furthercompactingit.DuringXchromosomeinactivation,anothergenefornoncodingRNA,Tsix,onXi,isdownregulated,buttheXistandTsixgenesneedtointeractwitheachotherforXchromosomeinactivationtotakeplace.TheseinteractionsaremediatedbyaregionofDNAcalledtheX-pairingregion(Xpr),whichisfoundabout200kilobasesupstreamofXist.ResearchindicatesthattransinteractionsbetweenXprregionsresultinhigherXistRNAlevels(Figure1). Infemales,differentialmethylationpatternsareerasedatsomepointandreestablishedbasedontherandomselectionofoneoftheXchromosomesinthelateblastocyst(Arieletal.,1995;Ngetal.,2007).ThemechanismforthisprocessinvolvestranscriptionofthegenesTsixandXiteandtheinvolvementofachromatininsulator,calledCtcf,intheX-inactivationcenter(Xuetal.,2007). Despitewhatweknowaboutgeneimprinting,Xchromosomeinactivation,DNAmethylation,andthevarioustranscriptionfactorsinvolved,muchneedstobediscoveredbeforewecanfullyexplainanyoftheseprocessesandhowthemessagetoexpressaspecificgenebasedontheparentalsourceistransmitted.AlthoughimprintingandXinactivationbothresultindecreasedgeneexpression,itisimportanttonotethatthemechanismsutilizedarecompletelydistinct,revealingthediversityofcellularprocessesthatactas"switches"tokeepgeneexpressioninthe"off"positionforspecificloci.Gainingamoredetailedunderstandingoftheseswitcheswillopendoorsformedicalresearchonthedeterminantsofvariousdiseasesandthecausesofanomaliesinembryonicdevelopment,inadditiontoleadingtoadvancesinstem-cellandcloningresearch. ReferencesandRecommendedReading Ariel,M.,etal.Gamete-specificmethylationcorrelateswithimprintingofthemurineXistgene.NatureGenetics9,312–315(1995)doi:10.1038/ng0395-312(linktoarticle) Barlow,D.Gameticimprintinginmammals.Science270,1610–1613(1995)doi:10.1126/science.270.5242.1610 Barlow,D.P.,etal.Themouseinsulin-likegrowthfactortype-2receptorisimprintedandcloselylinkedtotheTmelocus.Nature349,84–87(1991)doi:10.1038/349084a0(linktoarticle) Bartolomei,M.S.,etal.ParentalimprintingofthemouseH19gene.Nature351,153–155(1991).doi:10.1038/351153a0(linktoarticle) DeChiara,T.M.,etal.Parentalimprintingofthemouseinsulin-likegrowthfactorIIgene.Cell64,849–859(1991) McGrath,J.,&Solter,D.Completionofmouseembryogenesisrequiresboththematernalandpaternalgenomes.Cell37,179–183(1984) Ng,K.,etal.Xistandtheorderofsilencing.EMBOReports8,34–39(2007)doi:10.1038/sj.embor.7400871 Sleutels,F.,etal.Thenon-codingAirRNAisrequiredforsilencingautosomalimprintedgenes.Nature415,810–813(2002)doi:10.1038/415810a(linktoarticle) Surani,M.A.H.,etal.Developmentofreconstitutedmouseeggssuggestsimprintingofthegenomeduringgametogenesis.Nature308,548–550(1984)doi:10.1038/308548a0(linktoarticle) Xu,N.,etal.EvidencethathomologousX-chromosomepairingrequirestranscriptionandCtcfprotein.NatureGenetics39,1390–1396(2007)doi:10.1038/ng.2007.5(linktoarticle) Outline | Keywords | AddContenttoGroup ArticleHistory Close Share | Cancel Revoke | Cancel Keywords KeywordsforthisArticle AddkeywordstoyourContent Save | Cancel FlagInappropriate TheContentis: Objectionable Explicit Offensive Inaccurate Comments FlagContent | Cancel Close share Close Digg MySpace Google+ StumbleUpon EmailyourFriend YourFirstName * YourLastName * YourEmailAddress * YourFriend'sEmailaddress * YourMessage* Submit | Cancel * Required Close Thiscontentiscurrentlyunderconstruction. 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