EPIGENETICS表观遗传学

EpigeneticsAnypotentiallystableandheritablechangeingeneexpressionthatoccurswithoutachangeinDNAsequence“epigenetics”mean?•Literally,epigeneticsmeansabove,orontopof,genetics.•UsuallythismeansinformationcodedbeyondtheDNAsequence,suchasincovalentmodificationstotheDNAormodificationstothechromatinstructure.TranscriptionEpigeneticSilencingWhatdoes“epigenetics”mean?Practically,epigeneticsdescribesphenomenainwhichgeneticallyidenticalcellsororganismsexpresstheirgenomesdifferently,causingphenotypicdifferences.GeneticallyidenticalcellsorindividualsDifferentepigeneticmodificationsleadingtodifferentexpressionpatternsDifferentphenotypesXXXchromosomeinactivationinvolvesepigeneticsilencingXXXXXXXXXXXXXXXXXXXXXXXXXInfemalemammals,onecopyoftheXchromosomeineachcellisepigeneticallyinactivated.Furcolorincatsisdeterminedinpartbyorange,anX-linkedgene.Afemalecatthatisheterozygousfortheorangegeneshowsblackandorangepatches,correspondingtowhichXchromosomeisactive.Photocredit:DrLXXEpigeneticprogramminginplantshelpssilencetransposonsandmaintaincentromerefunctionPhotobyDamonLisch,inGross,L.(2006)Transposonsilencingkeepsjumpinggenesintheirplace.PLoSBiology4(10):e353.PhotoscourtesyoftheBarbaraMcClintockPapers,AmericanPhilosophicalSociety.Zhang,W.,etal.(2008)PlantCell20:25-34..EpigeneticprogramminginplantshelpscontroldevelopmentaltransitionsEmbryonicdevelopmentVegetativedevelopmentReproductivedevelopmentVegetativetoreproductivetransitionEmbryonictovegetativetransitionLectureOutlineEpigeneticmarksandtheirmaintenance•DNAmethylation•HistonemodificationsEpigeneticgenomeregulationinplants•Transposonsilencing•Controloffloweringtime•Controlofimprintedgenes•Genesilencingintrans;paramutation•ResettingtheepigenomeEpigeneticmarksandtheirmaintenanceTranscriptionEpigeneticSilencingEukaryoticDNAispackagedinnucleosomes~147bpDNA+8histones:2eachH2AH2BH3H4Approximately147basepairsofDNAwrappedaroundahistoneoctamerChromosomesconsistofheterochromatinandeuchromatinDenselypackagedheterochromatinLessdenselypackagedeuchromatinDNAaroundthecentromereisusuallypackagedasheterochromatin.CENTROMEREHeterochromatinandeuchromatinformdistinctdomainsinnucleiEuchromatinDAPIDNAstainMergedCentromericheterochromatinDeal,R.B.,Topp,C.N.,McKinney,E.C.,andMeagher,R.B.(2007)RepressionoffloweringinArabidopsisrequiresactivationofFLOWERINGLOCUSCexpressionbythehistonevariantH2A.Z.PlantCell19:74-83.EpigeneticmodificationsEpigeneticmodificationsinclude:–CytosinemethylationofDNA–HistonemodificationsCollectively,thesechangescontributetothedistributionofDNAintosilent,heterochromatinandactiveeuchromatinDNAmethylationONNH2N~ONNNH2~CH3cytosine5-methylcytosineTTCGCCGACTAAMethyl-cytosineDNAcanbecovalentlymodifiedbycytosinemethylation.DNAmethyltransferasesinArabidopsis•MET1(METHYLTRANSFERASE1)–5'-CG-3'sites•Silencingoftransposons,repetitiveelements,someimprintedgenes•CMT3(CHROMOMETHYLASE3)–5'-CHG-3'sites•(H=A,CorT)•Interactswithhistonemark•DRM1,DRM2(DOMAINSREARRANGED1and2)-5'-CHH-3'sites•Primarilytargetsrepetitiveelements•RequirestheactivetargetingofsiRNAsCGmethylationcanbepropagatedduringDNAreplicationMET15’ATGCGTACTATGCGTACTTACGCATGA“MAINTENANCE”METHYLATIONATGCGTACTTACGCATGAATGCGTACTTACGCATGA3’TACGCATGAATGCGTACTTACGCATGAAsymmetricmethylationsitesrequireadditionalinformationAsymmetricmethylationsitesaremaintained(andinitiated)byinformationonassociatedhistones,andanRNA-basedmechanism,RNA-directedDNAMethylation(RdDM),thatdirectsDNAmethylasestothesesites.5’ATGCAAACTATGCAAACTTACGTTTGA3’TACGTTTGAATGCAAACTTACGTTTGA}RequiresadditionalinformationtoremethylateSomesitesaremaintainedbysmallinterferingRNAs(siRNAs)5’ATGCAAACTsiRNAATGCAAACTTACGTTTGA3’TACGTTTGAATGCAAACTTACGTTTGADRM1/2ATGCAAACTTACGTTTGADifferentDNAmethylasesactondifferentsitesInthemet1mutant,CGmethylationisabolished,revealingthatMET1issolelyresponsibleforCGmethylationLister,R.,O’Malley,R.C.,Tonti-Filippini,J.,Gregory,B.D.,Berry,C.C.,Millar,A.H.,andEcker,J.R.(2008).Highlyintegratedsingle-baseresolutionmapsoftheepigenomeinArabidopsis.Cell133:523–536.DifferentDNAmethylasesactondifferentsitesBycontrast,inthetriplemutantofdrm1,drm2andcmt3,(ddc)nearlyallnon-CGmethylationisabolished,revealingtherolesofthesegenesinnon-CGmethylation.Lister,R.,O’Malley,R.C.,Tonti-Filippini,J.,Gregory,B.D.,Berry,C.C.,Millar,A.H.,andEcker,J.R.(2008).Highlyintegratedsingle-baseresolutionmapsoftheepigenomeinArabidopsis.Cell133:523–536.HeterochromatinDNAishighlymethylatedReprintedfromZhang,X.,etal.(2006)Genome-widehigh-resolutionmappingandfunctionalanalysisofDNAmethylationinArabidopsis.Cell126:1189–1201withpermissionfromElsevier.DNAmethylationisdensestattherepetitiveelementsaroundthecentromere.BLUE=GenedensityRED=RepetitiveelementdensityBROWN=MethylatedDNAinamet1mutantGREEN=MethylatedDNAHeterochromatinDNAishighlymethylatedReprintedfromZhang,X.,Yazaki,J.,Sundaresan,A.,Cokus,S.,Chan,S.W.-L.,Chen,H.,Henderson,I.R.,Shinn,P.,Pellegrini,M.,Jacobsen,S.E.,andEcker.,J.R.(2006)Genome-widehigh-resolutionmappingandfunctionalanalysisofD