第三节表观基因组学演示文稿

目前一页\总数八十七页\编于七点（优选）第三节表观基因组学目前二页\总数八十七页\编于七点epigenomicsreferstomoreglobalanalysesofepigeneticchangesacrosstheentiregenome.Aberrantepigeneticmechanismsareinvolvedinthedevelopmentofmanydiseases,includingcancer.Epigenomics表观基因组学目前三页\总数八十七页\编于七点（一）原核和真核的甲基化位点一、DNA甲基化目前四页\总数八十七页\编于七点N6-甲基腺嘌呤目前五页\总数八十七页\编于七点5-甲基胞嘧啶目前六页\总数八十七页\编于七点目前七页\总数八十七页\编于七点目前八页\总数八十七页\编于七点NNNH2OOH2COONHNOOOH2COOdeoxycytosinedeoxyuracil1’2’3’4’5’123456CH3thymineglycosidicbond5-甲基胞嘧啶与突变热点（hot-spot)目前九页\总数八十七页\编于七点From2%to7%ofthecytosinesofanimalcellDNAaremethylated(thevaluevarieswiththespecies).MostofthemethylgroupsarefoundinCG"doublets"onbothstrandsand,infact,themajorityoftheCGsequencesaremethylated.目前十页\总数八十七页\编于七点DNAmethyltransferase(DNAMTase)AfamilyofenzymesthatcatalyzethetransferofamethylgrouptoDNAMTasescanbedividedintothreedifferentgroupsonthebasisofthechemicalreactionstheycatalyze:

m6A-thosethatgenerateN6-methyladenine

m4C-thosethatgenerateN4-methylcytosine

m5C-thosethatgenerateC5-methylcytosine

m6Aandm4Cmethyltransferasesarefoundprimarilyinprokaryotes.m5Cmethyltransfereasesarefoundinsomelowereukaryotes,inmosthigherplants,andinanimalsbeginningwiththeechinoderms(棘皮类动物).（二）从头甲基化与甲基化维持DenovoandmaintenanceDNAMTasesanddemethylation目前十一页\总数八十七页\编于七点ThreeactiveDNAmethyltransferase(DNMT)havebeenidentifiedinmammals.TheyarenamedDNMT1，DNMT3A,andDNMT3B.DNAmethylationatthecytosineinCpGdinucleotidesisinitiateddenovobytheDNAmethyltransferases(DNMT)3Aand3B.DNMT1playsaprimaryroleinmaintainingthemethylationstateinthedaughterstrands.

DemethylationisthoughttooccurbyreductionofDNMT1activityorbyexcisionrepairmechanismsafterdeaminationofmethylcytosine(meC)tocreateaT:Gmismatch.Recentfindingssuggestthatthemethyl-DNAbindingprotein4(MBD4)maymediatedemethylationbyahormonallyregulatedmechanismthatdoesnotinvolvedeaminationofmeCbutratherinvolvestheDNAglycosylaseactivityofMBD4followedbyabaseexcisionrepairmechanism.目前十二页\总数八十七页\编于七点DNAMethylationIsPerpetuatedbyaMaintenanceMethylase

Replicationconvertsafullymethylatedsitetoahemimethylatedsite.Hemimethylatedsitesareconvertedtofullymethylated

sitesbyamaintenancemethylase.目前十三页\总数八十七页\编于七点TheabsenceofDnmtlinmousecauseswidespreaddemethylationatpromoters,andweassumethisislethalbecauseoftheuncontrolledgeneexpression.Thereisonemaintenancemethylase(Dnmtl)inmouse,anditisessential:mouseembryosinwhichitsgenehasbeendisrupteddonotsurvivepastearlyembryogenesis.目前十四页\总数八十七页\编于七点DNAmethylationanddemethylation.HandyDEetal.Circulation2011;123:2145-2156Copyright©AmericanHeartAssociation目前十五页\总数八十七页\编于七点EpigeneticEffectsCanBeInherited

Astateofmethylationcanbeperpetuatedthroughanindefiniteseriesofsomaticmitoses.Methylationcanalsobeperpetuatedthroughmeiosis:forexample,inthefungusAscobolusthereareepigeneticeffectsthatcanbetransmittedthroughbothmitosisandmeiosisbymaintainingthestateofmethylation.Inmammaliancells,epigeneticeffectsarecreatedbyresettingthestateofmethylationdifferentlyinmaleandfemalemeioses.目前十六页\总数八十七页\编于七点Aselfperpetuatingproteinstatemaybeestablished.Thismightinvolveassemblyofaproteincomplex,modificationofspecificprotein(s),orestablishmentofanalternativeproteinconformation.Situationsinwhichepigeneticeffectsappeartobemaintainedbymeansofproteinstatesarelesswellunderstoodinmolecularterms.目前十七页\总数八十七页\编于七点目前十八页\总数八十七页\编于七点

hemimethylated目前十九页\总数八十七页\编于七点目前二十页\总数八十七页\编于七点（三）CpG岛CpGIslandsDefinitionofCpGisland:

CpGislands(CGIs)areclustersofCpGdinucleotidesinGC-richregions.

"p"indicatesthat"C"and"G"areconnectedbyaphosphodiesterbond.

目前二十一页\总数八十七页\编于七点DNAmethylationcausesC→TlowoccurrenceofCpGdinucleotidesinvertebratesExpectationis6.25%randomlyActually1%oftotalsequence目前二十二页\总数八十七页\编于七点Islandcriterion:Observed/expectedCpGratio,G+Ccontent,minimumislandlengthandminimumnumberofCpGs(asGandCpGpoorandC-richregionswillmeettheO/Ecriterion)

CpGislandswerepredictedbysearchingthesequenceonebaseatatime,scoringeachdinucleotide(+17forCGand-1forothers)andidentifyingmaximallyscoringsegments.Eachsegmentwasthenevaluatedforthefollowingcriteria:GCcontentof50%orgreater,lengthgreaterthan200bp,ratiogreaterthan0.6ofobservednumberofCGdinucleotidestotheexpectednumberonthebasisofthenumberofGsandCsinthesegment.TheCpGcountisthenumberofCGdinucleotidesintheisland.ThePercentageCpGistheratioofCpGnucleotidebases(twicetheCpGcount)tothelength.TheratioofobservedtoexpectedCpGiscalculatedaccordingtotheformula(citedinGardiner-Gardenetal.(1987)):Obs/ExpCpG=NumberofCpG*N/(NumberofC*NumberofG)whereN=lengthofsequence.目前二十三页\总数八十七页\编于七点LeptingeneCpGislandproximalpromoterregion.BouchardLetal.DiaCare2010;33:2436-2441Copyright©2011AmericanDiabetesAssociation,Inc.目前二十四页\总数八十七页\编于七点between50-60%ofallgeneshaveaCpGislandinitspromoterregionsAlmostallhousekeepinggeneshaveaCpGislandCpGislandsareusuallyhypomethylated(undermethylated)butaberrantmethylationoftheseregionsplaysanimportantroleinepigeneticformationofmanycancertypes.CpGislandsareimportant“attributes”intheinsilicodetectionofpromotersandtopredictmethylationprobabilities.目前二十五页\总数八十七页\编于七点

CpGmethylationcansuppresstranscriptionFirst,directlyblockDNArecognitionandbindingbysometranscriptionfactors.Alternatively,otherfactorsmaypreferentiallybindtomethylatedDNA,blockingtranscriptionfactoraccess.（四）DNA甲基化调节基因表达目前二十六页\总数八十七页\编于七点Tissue-specificgeneswerefoundtobehighlymethylatedinmosttissuesamplesbutundermethylatedintheirtissueofexpression.Atthesametime,housekeepinggeneswereshowntohaveauniqueCpGislandpromoterstructure,whichisconstitutivelyunmethylatedineverycell.目前二十七页\总数八十七页\编于七点TranscriptionalgenesilencingbyCpGmethylationrestrictstheexpressionofsometissue-specificgenesduringdevelopmentanddifferentiation.Inearlyembryogenesis,methylationiserasedthroughoutthegenomeandthenreestablishedinallbutCpGislands.CpGislandsremainhypomethylateduntillaterindevelopment,whensomeofthembecomemethylated.Methylationisacrucialmechanismbywhichkeygenesaresuppressedduringdifferentiation.Methylationofnon-CpGcytosinesisalsocrucialforgeneregulationinembryonicstemcellsinparticular.DNA甲基化与分化、发育目前二十八页\总数八十七页\编于七点ActivehumangenestendtobeassociatedwithunmethylatedCpGsequences,whereastheCpGsininactiveregionsarealmostalwaysmethylated.DNAmethyltransferases(DNMTs)establishandmaintainDNAmethylationpatternsatspecificregionsofthegenome.Forexample:DNAmethylationandhistonemethylation?目前二十九页\总数八十七页\编于七点

ProposedmechanismofactionofDNAmethylationinhibitorsincancertherapy.Ahypotheticaltumor-suppressorgenepromoterisshownswitchingmethylationstatusfromunmethylatedandexpressedinnormaltissuetohypermethylatedandsilencedincancertissue.ThisswitchrequirestheactivityofDNAmethyltransferases(DNMT),whicharealsorequiredtomaintainthehypermethylatedstateaftereachroundofDNAreplication.InhibitorsofDNAmethyltransferaseswillresultinfailuretoremethylateafterDNAreplication,whicheventuallyleadstoappearanceoftotallyunmethylatedallelesthatreactivategeneexpression.Thiseffectongeneexpressionisthenhypothesizedtohavepleiotropiceffectsoncancercellbiology,includinginduction(orfacilitation)ofdifferentiation,apoptosis,senescence,andimmuneresponse,forexample.甲基化抑制剂5-氮-2′-脱氧胞苷Aza-dc目前三十页\总数八十七页\编于七点FIGURE1.Methylation-associatedmodelsofgenesilencing.

Generegulation:CodeofsilenceJuddC.RiceandC.DavidAllisNature414,258-261(15November2001)

a,DNAmethylation.CytosinenucleotidesaremethylatedbyaDNAmethyltransferase,increasingtheaffinityofmethyl-bindingproteinsforDNA.Someoftheseproteinsassociatewithrepressivecomplexesthatcontainhistonedeacetylases,resultingintheremovalofacetylgroupsfromlysine(K)residuesinthetailsofhistoneproteins,andgenesilencing.b,Histonemethylation.Acetylgroupsmustberemovedbeforelysineresidue9onhistoneH3canbemethylatedbyahistonemethyltransferase.Heterochromatin-associatedproteinspreferentiallybindmethylatedlysine9,leadingtogenesilencing.c,DNAmethylationandhistonemethylation.TamaruandSelker1showthatmethylationofhistoneH3lysine9isrequiredforsubsequentDNAmethylationandgenesilencinginfilamentousfungi.ItisnotknownwhetherornotthehistoneandDNAmethyltransferasesinteract.目前三十一页\总数八十七页\编于七点1.组蛋白的乙酰化2.组蛋白的甲基化3.组蛋白的磷酸化

4.组蛋白的泛素化5.组蛋白的SUMO二、组蛋白修饰AccesstonucleosomalDNAisgovernedbytwomajorclassesofproteincomplexes:Covalenthistone-modifyingcomplexes.ATP-dependentchromatinremodelingcomplexes.目前三十二页\总数八十七页\编于七点目前三十三页\总数八十七页\编于七点Histoneacetyltransferase(HATs)Histonedeacetylase(HDACs)Figure1:DNAmethylationandhistoneacetylationaretwocriticalepigeneticmechanismscontrollingchromatinstructureandfunctioninpostmitoticmammalianneurons.NatureNeuroscience13,405–406(2010)Ac,acetylgroup;Me,methylgroup.目前三十四页\总数八十七页\编于七点HypermethylatedDNArecruitssilencingtranscriptionchromatinremodelingcomplexeswithhistonedeacetylases(HDACs)andpromoteschromatincondensation.HypomethylatedDNAunfoldsintoa'beads-on-a-string'structureinwhichhistonesareaccessibleforchromatinremodelingfactorssuchasCREB-bindingproteinhistoneacetyltransferase(CBPHAT),thetranscriptionalcoactivatorimplicatedinepigeneticmechanismscontrollingmemoryconsolidation.

目前三十五页\总数八十七页\编于七点CREB(cAMPresponseelement-bindingprotein)

CREB-bindingprotein(CBP)andp300arebelievedtoparticipateintheactivitiesofhundredsofdifferenttranscriptionfactorsNature.1996Dec19-26;384(6610):641-3.TheCBPco-activatorisahistoneacetyltransferase.BannisterAJ1,KouzaridesT.TheCBPproteinactsasatranscriptionaladaptorformanydifferenttranscriptionfactorsbydirectlycontactingDNA-boundactivators.OnemechanismbywhichCBPisthoughttostimulatetranscriptionisbyrecruitingthehistoneacetyltransferase(HAT)P/CAFtothepromoter.HereweshowthatCBPhasintrinsicHATactivity.TheHATdomainofCBPisadjacenttothebindingsiteforthetranscriptionalactivatorE1A.AlthoughE1AdisplacesP/CAFfromCBP,itdoesnotdisrupttheCBP-associatedHATactivity.ThusE1AcarriesHATactivitywhencomplexedwithCBP.TargetingCBP-associatedHATactivitytospecificpromotersmaythereforebeamechanismbywhichE1Aactsasatranscriptionalactivator.目前三十六页\总数八十七页\编于七点1.主要发生在蛋白质的赖氨酸（K）上2.可逆的生化反应：A.HistoneacetyltransferaseHATB.HistonedeacetylaseHDAC3.分子效应：中和赖氨酸上的正电荷，增加组蛋白与DNA的排斥力4.生物学功能：A.基因转录活化

B.DNA损伤修复组蛋白的的乙酰化目前三十七页\总数八十七页\编于七点

HAT通过在组蛋白的N端赖氨酸残基上引入疏水的乙酰基，使DNA与组蛋白间的静电引力和空间位阻增大，二者间的相互作用减弱，染色质呈转录活性结构，DNA易于解聚、舒展，有利于转录因子与DNA模板相结合，进而激活转录。相反，HDAC使去乙酰化后带正电的组蛋白与带负电的DNA紧密结合，染色质呈致密卷曲的阻抑结构，可抑制转录。组蛋白乙酰化主要作用原理目前三十八页\总数八十七页\编于七点组蛋白的甲基化Lysineandarginineresiduesbothcontainaminogroups,whichconferbasicandhydrophobiccharacteristics.Lysineisabletobemono-,di-,ortrimethylatedwithamethylgroupreplacingeachhydrogenofitsNH3+group.WithafreeNH2andNH2+group,arginineisabletobemono-ordimethylated.目前三十九页\总数八十七页\编于七点

histonecodehypothesisThecriticalconceptofthehistonecodehypothesisisthatthehistonemodificationsservetorecruitotherproteinsbyspecificrecognitionofthemodifiedhistoneviaproteindomainsspecializedforsuchpurposes,ratherthanthroughsimplystabilizingordestabilizingtheinteractionbetweenhistoneandtheunderlyingDNA.Theserecruitedproteinsthenacttoalterchromatinstructureactivelyortopromotetranscription.Differentdegreesofresiduemethylationcanconferdifferentfunctions,asexemplifiedinthemethylationofthecommonlystudiedH4K20residue.MonomethylatedH4K20(H4K20me1)isinvolvedinthecompactionofchromatinandthereforetranscriptionalrepression.However,H4K20me2isvitalintherepairofdamagedDNA.Whendimethylated,theresidueprovidesaplatformforthebindingofprotein53BP1involvedintherepairofdouble-strandedDNAbreaks.H4K20me3isobservedtobeconcentratedinheterochromatinandreductionsinthistrimethylationareobservedincancerprogression.Therefore,H4K20me3servesanadditionalroleinchromatinrepression.[7]目前四十页\总数八十七页\编于七点三、染色质重塑Chromatinisadynamicmaterial;chromatinstructurescanrepresstranscriptionandtheirremodelingaccompaniesactivation.目前四十一页\总数八十七页\编于七点二聚体：H3&H4、H2A&H2B染色质的组装目前四十二页\总数八十七页\编于七点四聚体VS八聚体染色质的组装目前四十三页\总数八十七页\编于七点DNA序列缠绕在核心组蛋白的八聚体上染色质的组装目前四十四页\总数八十七页\编于七点染色体染色质的组装目前四十五页\总数八十七页\编于七点染色体的组装染色质的组装目前四十六页\总数八十七页\编于七点ThestructuresofentirechromosomesareinfluencedbyinteractionswithproteinsoftheSMC(structuralmaintenanceofchromosome)

Condensins：areinvolvedwiththecontrolof

overall

structure,andareresponsible

forthecondensationintocompactchromosomesatmitosis.Cohesins：areconcernedwithconnections

between

sisterchromatidsthatmustbereleasedatmitosis.目前四十七页\总数八十七页\编于七点核小体结构改变目前四十八页\总数八十七页\编于七点DefinitionofChromatinremodeling

Dynamicstructuralchangestoeukaryoticchromatinoccurringthroughoutthecelldivisioncycle.Thesechangesrangefromthelocalchangesnecessaryfortranscriptionalregulationtoglobalchangesnecessaryforchromosomesegregation.Chromatinremodelingisanepigeneticphenomenon.ChromatinRemodelinginvolvesalterationsofthecontentoractivityofDNA-bindingandchromatin-associatedproteinsthataffectthefunctionandhigherorderconformationalstateofchromatin,aswellastheactivityofspecificgenesorfunctionalDNAregions.ThemechanismsinvolvedwithmakingtheDNAinCHROMATINmoreorlessaccessibletotranscriptionmachinery.目前四十九页\总数八十七页\编于七点Theprocessofgenetranscriptionregulationisstronglylinkedtothephysicalpackagingofthechromatin.Thechromatiniscontinuouslypackedandunpacked,aprocessknownaschromatinremodelling,whichisgovernedbythechemicalmodificationsencodedinthehistonetailsandbythe

physicalmovement

ofthenucleosomes.目前五十页\总数八十七页\编于七点Chromatinremodelingcomplexesinthedynamicregulationoftranscription:Inthepresenceofacetylatedhistones(HATmediated)andabsenceofmethylase(HMT)activity,chromatinislooselypackaged.Additionalnucleosomerepositioningbychromatinremodelercomplex,SWI/SNFopensupDNAregionwheretranscriptionmachinerayproteins,likeRNAPolII,transcriptionfactorsandco-activatorsbindtoturnongenetranscription.IntheabsenceofSWI/SNF,nucleosomescannotmovefartherandremaintightlyalignedtooneanother.AdditionalmethylationbyHMTanddeacetylationbyHDACproteinscondensesDNAaroundhistonesandthus,makeDNAunavailableforbindingbyRNAPolIIandotheractivators,leadingtogenesilencing.目前五十一页\总数八十七页\编于七点Whatdoes‘chromatinremodeling’mean?JeffD.AalfsaandRobertE.Kingston

,aaDeptofMolecularBiology,MassachusettsGeneralHospital,Boston,MA02114,USA;andDeptofGenetics,HarvardMedicalSchool,Boston,MA02115,USA.

TrendsinBiochemicalSciencesVolume25,Issue11,1November2000,Pages548-555..Theregulatedalterationofchromatinstructure,termed‘chromatinremodeling’,canbeaccomplishedbycovalentmodificationofhistones

orbytheactionofATP-dependentremodelingcomplexes.Avarietyofmechanismscanbeusedtoremodelchromatin;someactlocallyonasinglenucleosomeandothersactmorebroadly.Itiscriticaltoestablishadirectconnectionbetweentheremodelingeventsobservedinvivoandthemechanisticcapabilitiesofremodelingcomplexesinvitro.目前五十二页\总数八十七页\编于七点ATP酶依赖的染色质重塑：在染色质重塑复合物或重塑因子(remodelers)介导下，应用ATP水解的能量移动、松解、排出或重建核小体，调控染色质的包装状态。在真核生物这一需能的、染色质的动态结构改变，范围从转录调节所需的局部改变，至染色体分离所需的整体的改变。ATP酶依赖的染色质重塑目前五十三页\总数八十七页\编于七点

染色质重塑因子：是一组以ATP酶为催化中心的、多蛋白亚单位组成的复合体，依靠水解ATP提供能量完成染色质结构的改变。

Thereareatleastfivefamiliesofchromatinremodelersineukaryotes:SWI/SNF,ISWI,NuRD/Mi-2/CHD,INO80andSWR1withfirsttworemodelersbeingverywellstudiedsofar,especiallyintheyeastmodel.AlthoughallofremodelerssharecommonATPasedomain,theirfunctionsarespecificbasedonseveralbiologicalprocesses(DNArepair,apoptosis,etc.).

染色质重塑因子(Remodeler)目前五十四页\总数八十七页\编于七点染色质重塑染色质重塑因子目前五十五页\总数八十七页\编于七点AtthecoreofachromatinremodelingcomplexeisanATPasecapableofDNAtranslocation.Bymovingnucleosomes,proteinsliketranscriptionfactorscangetaccesstoDNAthatwaspreviouslyunavailable,wrappedaroundnucleosomecores.目前五十六页\总数八十七页\编于七点AbromodomainisaproteindomainthatrecognizesacetylatedlysineresiduessuchasthoseontheN-terminaltailsofhistones.Thedomainitselfadoptsanall-αproteinfold,abundleoffouralphahelices.Achromodomainisproteinstructuraldomainofabout40-50aminoacidresidueswhichbindmethylatedhistones.目前五十七页\总数八十七页\编于七点Chromatinremodelingcomplexesinthedynamicregulationoftranscription:Inthepresenceofacetylatedhistones(HATmediated)andabsenceofmethylase(HMT)activity,chromatinislooselypackaged.Additionalnucleosomerepositioningbychromatinremodelercomplex,SWI/SNFopensupDNAregionwheretranscriptionmachinerayproteins,likeRNAPolII,transcriptionfactorsandco-activatorsbindtoturnongenetranscription.IntheabsenceofSWI/SNF,nucleosomescannotmovefartherandremaintightlyalignedtooneanother.AdditionalmethylationbyHMTanddeacetylationbyHDACproteinscondensesDNAaroundhistonesandthus,makeDNAunavailableforbindingbyRNAPolIIandotheractivators,leadingtogenesilencing.目前五十八页\总数八十七页\编于七点目前五十九页\总数八十七页\编于七点目前六十页\总数八十七页\编于七点Agreatdealofevidencepointstotheideathatthemajoreffectofmethylgroupsistomodelchromatinstructure,andthismaybecarriedoutatmanydifferentlevels.MicroinjectionexperimentshavedemonstratedthatagenetemplateinserteddirectlyintothenucleusofcellsincultureisinitiallyunaffectedbyDNAmethylation.Onlyafterthesesubstrateshavehadachancetogetpackagedintoachromosomalstructuredoesonebegintoseetheeffectsofthismodicationontranscription.

DNA甲基化影响染色质结构DNA甲基化、组蛋白修饰与染色质重塑目前六十一页\总数八十七页\编于七点ThemostconvincingevidenceforthisideacomesfromDNA-mediatedcelltransfectionstudiesshowingthatunmethylatedsubstratesarepackagedintoanopenchromatinstructurefollowingtheirintegrationintothegenome,whereastheexactsameDNAremainscompletelyresistanttoDNaseIifitismethylated.BecausetheseexperimentswerecarriedoutusingbacterialDNAsequencesthatdonotharboranyeukaryoticregulatoryinformation,onecanconcludethatmethylmoietiesthemselvesmustberesponsibleforgeneratingaclosedchromatinstructureregardlessofsequencecontext.目前六十二页\总数八十七页\编于七点

1.辅助染色质组装：移开已存在的组蛋白八聚体，为新沉积组蛋白八聚体预留空间；

2.重塑因子作用于核小体的排列，结果使原被组蛋白八聚体封闭的DNA结合蛋白(DNA-bindingprotein，DBP)的位点暴露出来，能引发核小体滑动(重定位)、核小体排出或局部松解；

3.协助改变核小体成分：核小体的成分通过二聚体的置换而改变，如H2A、H2B被含有组蛋白变体的二聚体所交换；二聚体排出亦可改变核小体的组成。染色质重塑导致的几种结果:目前六十三页\总数八十七页\编于七点五、DNA甲基化与遗传印记目前六十四页\总数八十七页\编于七点Agermcellisanybiologicalcellthatgivesrisetothegametesofanorganismthatreproducessexually.Inmanyanimals,thegermcellsoriginatenearthegutofanembryoandmigratetothedevelopinggonads.There,theyundergocelldivisionoftwotypes,mitosisandmeiosis,followedbycellulardifferentiationintomaturegametes,eithereggsorsperm.Unlikeanimals,plantsdonothavegermcellssetasideinearlydevelopment.Instead,germcellscancomefromsomaticcellsintheadult(suchasthefloralmeristemoffloweringplants)fromWikipediaAgermcell：Anovumoraspermcelloroneofitsdevelopmentalprecursors.maternal母亲的，得自母亲的paternal父亲的；得自父亲的；parental[pəˈrɛntl:]父母的；亲代的；生殖细胞（germcell）是多细胞生物体内能繁殖后代的细胞的总称，包括从原始生殖细胞直到最终已分化的生殖细胞。原生殖细胞（Primordialgermcell,PGC）原肠胚时含有生殖质的细胞称为原生殖细胞。此以前的生殖细胞称为预定原生殖细胞。所以原生殖细胞是生殖细胞的祖先细胞.spermatocyteoocyte目前六十五页\总数八十七页\编于七点Embryogenesis:DemethylationofthezygoticpaternalgenomeWolfgangMayer，AlainNiveleau,JörnWalter,ReinaldFundele&ThomasHaafAbstractInmammals,bothparentalgenomesundergodramaticepigeneticchangesafterfertilizationtoformthediploidsomaticgenome.Hereweshowthatthepaternalgenomeinthemouseissignificantlyandactivelydemethylatedwithin6–8hoursoffertilization,beforetheonsetofDNAreplication,whereasthematernalgenomeisdemethylatedafterseveralcleavagedivisions.Thisactivedemethylationofthepaternalgenomemaybeassociatedwithepigeneticremodellingofspermchroma-tin,inordertoestablishparent-specificdevelopmentalprogrammesduringearlyembryogenesis.Nature403,501-502(3February2000)目前六十六页\总数八十七页\编于七点Theprocessoffertilizationintheovumofamouse目前六十七页\总数八十七页\编于七点

DNAMethylationIsResponsibleforImprintingPaternalandmaternalallelesmayhavedifferentpatternsofmethylationatfertilization.Methylationisusuallyassociatedwithinactivationofthegene.Whengenesaredifferentiallyimprinted,survivaloftheembryomayrequirethatthefunctionalalleleisprovidedbytheparentwiththeunmethylatedallele.Imprintedgenesoccurinclustersandmaydependonalocalcontrolsitewheredenovomethylationoccursunlessspecificallyprevented.目前六十八页\总数八十七页\编于七点FIGURE31.22Thetypicalpatternforimprintingisthatamethylatedlocusisinactive.Ifthisisthematernalallele,onlythepaternalalleleisactive,andwillbeessentialforviability.Themethylationpatternisresetwhengametesareformed,sothatallspermhavethepaternaltypeandalloocyteshavethematernaltype.目前六十九页\总数八十七页\编于七点基因组印记的建立胚囊目前七十页\总数八十七页\编于七点SchematicofImprintingPrimordialgermcell原始生殖细胞目前七十一页\总数八十七页\编于七点Thepatternofmethylationofgermcellsisestablishedineachsexduringgametogenesisbyatwo-stageprocess:Firsttheexistingpatterniserasedbyagenome-widedemethylation,andthenthepatternspecificforeachsexisimposed.目前七十二页\总数八十七页\编于七点目前七十三页\总数八十七页\编于七点亲本印记，配子印记及基因组印记在一些哺乳类(包括鼠、人、绵羊)的若干常染色体基因的传递过程中,有些基因只有父方等位基因有转录活性,而母方的同一基因则始终处于缄默状态;另一些性状则相反,来自母方的基因有转录活性,而父方基因保持缄默。这种类型基因的表达结果是子代的某些表型特征或者完全模仿父本,或者完全模仿母本。一般称这种基因的表型效应为亲本印记(Parentalimprinting),称携带这种基因的配子为配子印记(Gameticimprinting),相应的基因组印记称为基因组印记（Genomicimprinting)

目前七十四页\总数八十七页\编于七点概念：基因组印记基因组印记是指二倍体细胞中的父母亲特异的基因表达。Describesthedifferentialexpressionofgeneticmaterialatchromosomal/alleliclevel,dependingonthatmaterialbeingmaternalorpaternalinorigin.两个等位基因中只有一个基因表达；可遗传的修饰，并且不改变基因序列的组成GenomicimprintingisanepigeneticprocessthatmarksDNAinasexdependentmanner,resultinginthedifferentialexpressionofagenedependingonitsparentoforigin.目前七十五页\总数八十七页\编于七点基因组印记基因组印迹是基因遗传外重编程决定的父源或母源特异等位基因的差异表达,这种依赖于亲本起源的特殊等位基因上产生修饰并引起等位基因表达不对称的现象称为基因组印迹。基因组印迹是贯穿于生命生长和发育整个过程的重要生物学机制,印迹基因的错误转录和表达导致胚胎发育异常和多种印迹疾病。目前七十六页\总数八十七页\编于七点TheeffectsofHuntington'sdiseasemaybesubjecttogenomicimprinting.目前七十七页\总数八十七页\编于七点在小鼠中已发现100多个印记基因，一般认为在人中具有大致相等数量的印记基因分析结果表明可能有更多的印记基因Oncethoughttoberestrictedtomammals,genomicimprintinghasbeendocumentedinangiosperm（被子植物）plants1970,zebrafish1995,insects,andC.elegans2004.Inplants,genesareimprintedprimarilyintheendosperm(胚乳）主要功能:出生前的生长发育;一般父系基因的表达可增强胚胎的发育能力，而母系基因的表达则减弱胚胎的发育能力目前七十八页\总数八十七页\编于七点Figure1.Imprinting,doublefertilization,andtheplantlifehistory.目前七十九页\总数八十七页\编于七点Justasinconventionalinheritance,genesforagiventraitarepasseddowntoprogenyfrombothparents.However,thesegenesare

epigeneticallymarkedbeforetransmission,alteringtheirlevelsofexpression.Theseimprintsarecreatedbeforegameteformationandareerasedduringthecreationofgermlinecells.Therefore,anewpatternofimprintingcanbemadewitheachgeneration.目前八十页\总数八十七页\编于七点Genesareimprinteddifferentlydependingontheparentaloriginofthechromosomethatcontainsthem.Inmice,theinsulin-likegrowthfactor2gene(Igf2)geneundergoesimprinting.Theproteinencodedbythisgenehelpstoregulatebodysize.Micethatpossesstwofunctionalcopiesofthisgenearelargerthanthosewithtwomutantcopies.Thesizeofmicethatareheterozygousatthislocusdependsontheparentfromwhichthewildtypeallelecame.Ifthefunctionalalleleoriginatedfromthemother,theoffspringwillexhibitdwarfism,whereasapaternalallelewillgenerateanormalsizedmouse.ThisisbecausethematernalIgf2geneisimprinted.ImprintingresultsintheinactivationoftheIgf2geneonthechromosomepas