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10/3/16 (2)TheroleofEpigenetic Inheritance • LamarckRevisited • Lamarckwasincorrectinthinkingthatthe inheritanceofacquiredcharactersisthemain mechanismofevolution(NaturalSelectionmore common) EpigeneticInheritance • However,wenowknowthattheinheritanceof acquiredcharactersdoeshappensometimes, throughtheinheritance ofepigeneticmodifications 1 Historicalperspective Epigenetics:termcoinedbyC.H.Waddingtonin1942.Alterations ingeneexpression,butwheretheDNAitselfremainsunchanged. Epigeneticmodificationshavebeenwidelyknownsincethe1970s. Notmuchintextbook,butwatch13minuteNOVAclipon epigenetics:http://www.pbs.org/wgbh/nova/body/epigenetics.html Epigeneticinheritance:However,thatepigeneticmodifications couldsometimesbeinherited isaveryrecentdiscovery Westilldonotknowhowwidespreadtransgenerational epigenetic inheritanceisinanyorganism Epigenetic Modifications • “Epigeneticmarks”(methylation,etc.)aremadeacrossthe genomeateachgenerationtodefinecelltypesandpatternsof geneexpressioninthedevelopingembryo.These“marks” definewhichgenesareturnedonandoff. • Marksfromthepreviousgenerationaretypicallyremovedinthe germline,toenabletotipotency ofcellsinearlyembryos • Epigeneticchangescouldbeenvironmentallyinduced • Occasionallythereprogrammingisbypassedandsome epigeneticmarksgetpassedon à LamarckianEvolution 4 EpigeneticInheritance EpigeneticInheritance:Alterationsingene expressionthatarepassedontothenext generation,butwheretheDNAitselfremains unchanged NOVAcliponepigenetics ifyouwantmorebackground: http://www.pbs.org/wgbh/nova/body/epigenetics.html DNAmethylation istypicallyremovedduringzygoteformationand re-establishedthroughsuccessivecelldivisionsduringdevelopment. 1 10/3/16 Implications: EpigeneticEffects: Thesamegenomecouldexpress differentphenotypes:Epigeneticdifferencescould resultinphenotypicdifferencesevenamong identicaltwins(clones) EpigeneticInheritance: Reallyrapidevolutioncould takeplacewithoutchangesinthegeneticcode (1)ClarificationofConcepts • Epigeneticeffects:typicallynotheritablechangesingeneexpression orcellularphenotypecausedbymechanismsotherthanchangesinthe underlyingDNAsequence.Examples:DNAmethylationandhistone deacetylation,bothofwhichservetosuppressgeneexpressionwithout alteringthesequenceofthesilencedgenes • Transgenerational epigeneticeffects:Theseareregardedas effectsonthephenotype(oronpatternsofgeneexpression)that aredetectedacrossmorethanonegenerationandthatcannotbe explainedbyMendelian genetics(orchangestotheprimaryDNA sequence).Example:transgenerational plasticity,maternaleffects. • Transgenerational epigeneticinheritance:Thistermrefersto effectsonphenotype(oronpatternsofgeneexpression)thatare passedfromonegenerationtothenextbymoleculesinthegerm cells andthatcannotbeexplainedbyMendelian genetics(orby changestotheprimaryDNAsequence). PhenotypicPlasticity Definition • Differencesinphenotypethatagenotypeexhibits acrossarangeofenvironments,becauseofchanges ingeneexpression • Changesingeneexpressioncouldbecauseby environmentalcuesinstigatingsignaltransduction... changesingeneexpressioncouldalsobecausedby epigeneticmodifications • Sometraitswithaplasticcomponent:intelligence, height,temperaturetolerance,salinitytolerance, musclemass… Outline (1)ClarificationofConcepts (2)EpigeneticModifications (3)EpigeneticInheritance (4)ExampleofEpigeneticInheritance EpigeneticModification(Effect) versus EpigeneticInheritance IfEpigeneticModifications occuralone,theyare NOTasignofEpigeneticInheritance ThechangesthatMATTERforevolution,whether theyareepigeneticorgenetic(mutations),arethose thatgetpassedontothenextgenerationthrough thegermline (eggsorsperm) Epigeneticmodificationsthatoccurinasingle generationareonetypeofphenotypicplasticity Acclimation (≠ Adaptation) 1) Result of Phenotypic Plasticity 2) Not heritable (Not inherited) 3) Short term or developmental response within a single generation 4) Arises through differential gene expression or other regulatory mechanism rather than natural selection 2 10/3/16 Exampleofphenotypic plasticity,causedby environmentalchange(not necessarilyepigenetic) Predator induced formation of helmets in Daphnia (2)EpigeneticModifications HebertandGrewe,1985 SomeTypesofEpigeneticmodifications (incompletelist) • ChromatinModification: epigeneticalterationofchromatin structure,affectinggeneexpression Examples: Methylation Histone Modifications(acetylation,deacetylation) ChromatinRemodelling • RNA-mediatedModifications: post-transcriptionalRNA modifications Examples: RNAinterference(RNAi)basedmechanism - RNAstrandsinterferewith thetranscriptionofDNAortranslationofmRNA -- OftensmallRNAs,oftenthosethattargettransposableelements -- Seemstooccurmainlyatretrotransposons andotherrepeated elements. Paramutations werefirstdiscoveredandstudiedinmaize(Zea mays)byR.A.Brink attheUniversityofWisconsin–Madison(DeptofGenetics)inthe1950s OriginalArticle: R.A.BrayandR.A.Brink.1966.MutationandParamutation attheRLocus inMaize.Genetics.54:137–149. ConsequencesofEpigeneticModifications: ChangesinGeneExpression -- Genomicimprinting: wheremethylation andhistone modifications altergeneexpressionwithoutalteringthegeneticsequence.When inherited,these“epigeneticmarks”areestablishedinthegermlineand aremaintainedthroughoutallsomaticcellsofanorganism. -- GeneSilencing:couldoccurthroughseveralmechanisms,suchas histonemodification,mRNAdestruction,orRNAinterference(RNAi). -- Paramutation:whereinteractionbetweentwoallelesatasinglelocus, resultsinaheritablechangeinexpressionofoneallelethatisinduced bytheotherallele.Mechanismisnotfullyunderstood,butcouldoccur viamethylation orregulatoryRNAs.Paramutation violatesMendel’s firstlaw,whichstatesthateachalleleremainscompletelyuninfluenced bytheother. ChromatinModification Portela &Esteller.2010.Epigeneticmodificationsand humandisease.NatureBiotechnology 28:1057–1068 3 10/3/16 Epigeneticmodifications Epigenetic Modifications DNAMethylation Examples: • Additionofamethylgroup(CH3) atthe5positionofcytosineà reducegeneexpression DNA Methylation: methyl groups are enzymatically added and removed, through the action of methylases and demethylases. The level of methylation generally correlates with the transcriptional state of a gene: active genes are less methylated than inactive genes DNAmethyltransferases • Inadultsomatictissues, methylation usuallyoccursinthe CpG islands,aCGrichregion, upstreamofthepromoter region. • Inembryonicstemcellsnon-CpG methylation isprevalent (significantcytosine-5methylation atCpA andCpT;Ramsahoye2000). Example of a type of Epigenetic Modification: DNA Methylation DNAmethylation iscarriedoutbya groupofenzymescalledDNA methyltransferases. Methyl groups are enzymatically added and removed to DNA, through the action of methylases and demethylases. The level of methylation generally correlates with the transcriptional state of a gene: active genes are less methylated than inactive genes Epigeneticmodifications DNAMethylation DNAmethyltransferases Theseenzymesnotonlydetermine theDNAmethylation patternsduring theearlydevelopment,butarealso responsibleforcopyingthese patternstothestrandsgenerated fromDNAreplication. 21 Epigeneticmodifications One way in which DNA Methylation suppresses gene expression DNAMethylation promoter gene • Crucialpartofnormalorganismaldevelopmentandcellular differentiationinhigherorganisms • Altersgeneexpressionpatternincells • Suppressesexpressionofviralgenesandotherdeleterious elementsthathavebeenincorporatedintothegenomeofthe hostovertime • Methylation atthepromotersiteorupstreamofthepromoter transcriptionfactor changeingeneexpression promoter gene • Playsacrucialroleinthedevelopmentofnearlyalltypesof cancer(hypermethylation,whichrepressestranscriptionofthe promoterregionsoftumorsuppressorgenes) • Mightbethemechanismforlearningandlongtermmemory storage • Methylation ofnucleotidesinaregulatoryelement,suchasthepromoter, or upstreamofthepromoter,couldleadtochangesingeneexpression. • Usually,suppressionofexpressionoccursduetointerferencewithbindingof thetranscriptionfactor. • Typicallymoremethylation leadstogreatersuppressionofgeneexpression 4 10/3/16 FactorsthatcouldaffectDNAMethylation • ExampleofDNAMethylation:DNAmethylation oftheagoutigeneinmicehavebeenfoundto causebrownskinnymice…demethylation ofthis gene(increasedexpressionofagouti)resultsin yellowfatmice TheEnvironment:suchasdiet toxins,vitamins,stress,affection (licking,hugging),etc.etc… • TheAgoutiviableyellow(Avy)alleleiscreatedbya retrotransposon insertionofanelement (intracisternal Aparticle,IAP)upstreamoftheagouti locus. • DNAmethylation oftheIAPpromoteratAvy reduces transcriptionoftheAvy gene(getbrownskinnymice) DNAMethylation: Childhoodtrauma • EarlychildhoodtraumacanleadtoDNAdemethylation ofthe FKBP5geneinhumanindividualsthatpossessparticular allelesatthisgene. • FKBP5regulatesglucocorticoid receptoractivityandstress response.Demethylation ofthe“AA”genotypeleadsto excessiveglucocorticoid receptoractivation. • Thosehomozygousforthe“A”alleleoftheFKBP5genewere morelikelytosufferfromdepression,post-traumaticstress disorder,oranxietydisordersinadulthood,iftheywere abusedaschildren(causingdemethylation atthislocus). http://usrexp-sandbox.nature.com/neuro/journal/v16/n1/full/nn.3275.html Klengel,T.etal.Allele-specificFKBP5 DNAdemethylation mediatesgene–childhood traumainteractions.NatureNeurosci.2Dec2012 Histone Modifications Histone Deacetylases/ Histone Acetyltransferase • Theabilityofaparticulartranscriptionfactortobindtoitstarget geneis,inpart,dependentonmodificationsthataremadetothe histone proteins • AbnormalactivityofHDACs hasbeenobservedinacute promyelocytic leukemia,acutemyelogenous leukemia,non-Hodgkin lymphoma,andsometypesofcolorectalandgastriccarcinoma 5 10/3/16 Histone Deacetylases/ Histone Acetyltransferase Histone Acetylation orDeacetylation:affectslevelofrelaxation ofthechromatinandlevelofgenetranscription. • Histone acetyltransferases (HATs): Acetylate Histones,enhance transcription; acetylation neutralizespositivechargesonthe histone bychangingaminesintoamidesanddecreasestheabilityof thehistones tobindtoDNA,allowinggeneexpression • Histone Deacetylases (HDACs): Deactylate Histones, repress transcription;removeacetylgroupsfromanε-N-acetyllysineamino acidonahistone SIRT1regulatesmany functionsinvolving apoptosisandcell survival • Forexample, cooperateswithHIC1 toregulateactivityof p53(tumor suppressorgene)and apoptosis Exampleofhistone deacetylase: Aging • Sirtuin orSir2proteins areaclassofproteinsthatpossess eitherhistonedeacetylase ormono-ribosyltransferase activity. • AsHistone Deacetylases,Sirtuins regulatetranscription • Sirtuins havebeenimplicatedininfluencingaging,stress resistance,insulinsignalingandmetabolism(energy efficiency),andapoptosisandcancersuppression • Caloricrestrictionà activatesirtuins à slowdownaging • Drugsthatactivatesirtuins mightalsoslowdownaging DNAMethylationandHistone Deacetylation:Goodparenting (transgenerational epigeneticeffect) Inrats,mothersthatengageinhighorlow amountsoflicking/groomingoftheirpups • Increasedmaternalcareresultsintwotypesofepigenetic changes:(1) acetylation ofhistones H3-K9,and(2) demethylation ofthetranscriptionfactor(NGFI-A)bindingsitetothepromoter oftheglucocorticoid receptorà higherGRactivity • Offspringthatreceivedhighlevelsoflicking/groomingshow lowerstressresponse(happyandcalm)andbecomegood mothersthatlicktheirpupsalot…leadingtothesameepigenetic patterns • Thus,thebehavioroflickingresultsinthesameepigenetic patternbeingpassedon http://blogs.bu.edu/ombs/2010/11/11/licking-rat-pups-the-genetics-of-nurture/ http://www.nature.com/neuro/journal/v7/n8/abs/nn1276.html DNAMethylation andHistone Deacetylation:Goodparenting • Thisisanimportantexampletoillustratethedifference betweenatransgenerational epigeneticeffectversus transgenerational epigeneticinheritance • Thisisatransgenerational epigeneticeffect(maternal effect),butNOTtransgenerational epigenetic inheritance (3)EpigeneticInheritance • Onlythoseepigeneticmodificationsthatare heritableviathegametes(germline)à leadto epigeneticinheritance. • ***Thisis NOTEpigenetic Inheritance becausethe behaviorispassedon,ratherthantheepigeneticmark itself...theepigeneticmarkisinducedbythebehavior oflickingateachgeneration 6 10/3/16 (3)EpigeneticInheritance • Mostepigeneticmodifications,i.e.epigeneticmarks,thatare establishedinmosttissuesduringanorganism’slifetimeare irrelevantwithrespecttothenextgeneration. «Thisisbecauseepigeneticmodificationsarenormallyerasedat eachgeneration.Forexample,DNAmethylation istypically removed(orpossiblyoxidized;Iqbal etal.2011)duringzygote formationandre-establishedthroughsuccessivecelldivisions duringdevelopment. «Andalsobecauseonlyepigeneticmodificationsofthemature gametes(andnotinothertissues)havethepotentialtocontribute tothephenotypeoftheoffspring,thenextgeneration. EpigeneticInheritance Alterationsingeneexpressionthatarepassed ontothenextgeneration,butwheretheDNA itselfremainsunchanged Stillanewfrontier(thisfieldisstillextremely new),withmanyexamplesinplantsandfewer concreteexamplesinanimals • Onlythoseepigeneticmodificationsthatareheritableviathe gametes(germline)à leadtoepigeneticinheritance. 38 ExamplesofEpigeneticInheritance ExamplesofEpigeneticInheritance FlowerSymmetry EpigeneticTriggerfortomatoripening InthetoadflaxLinaria vulgaris, radially symmetricflowers, ratherthanthetypical bilaterallysymmetricones,is causedbyDNAmethylation of theCYCLOIDEAgene,which controlstheformationofdorsal petals. • Sometomatoesdonotripenandremaingreen. • Thesetomatoeshaveaheritablecytosine hypermethylation oftheCnr genepromoter, whichinhibitsexpressionoftheCnr gene http://usrexp-sandbox.nature.com/nbt/journal/v31/n2/full/nbt.2497.html Hypermethylation oftheCnr promoterresultsininhibition ofRINtranscriptionfactorbinding,preventingCnr gene expressionandfruitripening. PotentialExamplesofEpigeneticInheritance (notconclusive) • MethylationatFKBP5 geneinHolocaustsurvivorsandtheir offspring.Thisgeneaffectsglucocorticoidresponse(stress response),andislinkedtoPTSDanddepression(Rachel Yehudaetal.2015)à needsmorestudy • Resultsarenotclearlyinterpretable (http://blogs.plos.org/biologue/2015/07/07/human-diseaseepigenomics-2-0/) • Miceexposedtotoxinspassonfearoftheodorofthat toxinontotheiroffspring(not100%conclusive) http://usrexp-sandbox.nature.com/nbt/journal/v31/n2/full/nbt.2497.html • ExamplesofEpigeneticInheritance aremuchmore commoninplantsandmoreconclusive 42 7 10/3/16 References Whichchangesallelesfrequencies? Whichchangesgenotypefrequencies? http://www.biologicalpsychiatryjournal.com/article /S0006-3223%2815%2900652-6/abstract http://www.nature.com/news/searching-chromosomes-for-thelegacy-of-trauma-1.15369 • Selection • GeneticDrift http://www.scientificamerican.com/article/descen dants-of-holocaust-survivors-have-altered-stresshormones/ • • • • http://www.nature.com/news/fearful-memories-haunt-mousedescendants-1.14272 http://usrexpsandbox.nature.com/nbt/journal/v31/n2/full/nbt.2497.html Inbreeding Recombination Mutations Migration(Geneflow) • Epigeneticmodifications 43 8