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10/3/16
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(2)TheroleofEpigeneticInheritance
• LamarckRevisited
• Lamarckwasincorrectinthinkingthattheinheritanceofacquiredcharactersisthemainmechanismofevolution(NaturalSelectionmorecommon)
• However,wenowknowthattheinheritanceofacquiredcharactersdoeshappensometimes,throughtheinheritance ofepigeneticmodifications
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EpigeneticInheritance
HistoricalperspectiveEpigenetics:termcoinedbyC.H.Waddingtonin1942.Alterationsingeneexpression,butwheretheDNAitselfremainsunchanged.
Epigeneticmodificationshavebeenwidelyknownsincethe1970s.Notmuchintextbook,butwatch13minuteNOVAcliponepigenetics:http://www.pbs.org/wgbh/nova/body/epigenetics.html
Epigeneticinheritance:However,thatepigeneticmodificationscouldsometimesbeinherited isaveryrecentdiscovery
Westilldonotknowhowwidespreadtransgenerational epigeneticinheritanceisinanyorganism
Epigenetic Modifications• “Epigeneticmarks”(methylation,etc.)aremadeacrossthe
genomeateachgenerationtodefinecelltypesandpatternsofgeneexpressioninthedevelopingembryo.These“marks”definewhichgenesareturnedonandoff.
• Marksfromthepreviousgenerationaretypicallyremovedinthegermline,toenabletotipotency ofcellsinearlyembryos
• Epigeneticchangescouldbeenvironmentallyinduced
• Occasionallythereprogrammingisbypassedandsomeepigeneticmarksgetpassedonà LamarckianEvolution
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EpigeneticInheritance
EpigeneticInheritance:Alterationsingeneexpressionthatarepassedontothenextgeneration,butwheretheDNAitselfremainsunchanged
NOVAcliponepigenetics ifyouwantmorebackground:http://www.pbs.org/wgbh/nova/body/epigenetics.html
DNAmethylation istypicallyremovedduringzygoteformationandre-establishedthroughsuccessivecelldivisionsduringdevelopment.
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Implications:
EpigeneticEffects: Thesamegenomecouldexpressdifferentphenotypes:Epigeneticdifferencescouldresultinphenotypicdifferencesevenamongidenticaltwins(clones)
EpigeneticInheritance: Reallyrapidevolutioncouldtakeplacewithoutchangesinthegeneticcode
Outline(1)ClarificationofConcepts
(2)EpigeneticModifications
(3)EpigeneticInheritance
(4)ExampleofEpigeneticInheritance
• Epigeneticeffects:typicallynotheritablechangesingeneexpressionorcellularphenotypecausedbymechanismsotherthanchangesintheunderlyingDNAsequence.Examples:DNAmethylationandhistonedeacetylation,bothofwhichservetosuppressgeneexpressionwithoutalteringthesequenceofthesilencedgenes
• Transgenerational epigeneticeffects:Theseareregardedaseffectsonthephenotype(oronpatternsofgeneexpression)thataredetectedacrossmorethanonegenerationandthatcannotbeexplainedbyMendelian genetics(orchangestotheprimaryDNAsequence).Example:transgenerational plasticity,maternaleffects.
• Transgenerational epigeneticinheritance:Thistermreferstoeffectsonphenotype(oronpatternsofgeneexpression)thatarepassedfromonegenerationtothenextbymoleculesinthegermcells andthatcannotbeexplainedbyMendelian genetics(orbychangestotheprimaryDNAsequence).
(1)ClarificationofConcepts
IfEpigeneticModifications occuralone,theyareNOTasignofEpigeneticInheritance
ThechangesthatMATTERforevolution,whethertheyareepigeneticorgenetic(mutations),arethosethatgetpassedontothenextgenerationthroughthegermline (eggsorsperm)
Epigeneticmodificationsthatoccurinasinglegenerationareonetypeofphenotypicplasticity
EpigeneticModification(Effect)versus EpigeneticInheritance
Definition• Differencesinphenotypethatagenotypeexhibitsacrossarangeofenvironments,becauseofchangesingeneexpression
• Changesingeneexpressioncouldbecausebyenvironmentalcuesinstigatingsignaltransduction...changesingeneexpressioncouldalsobecausedbyepigeneticmodifications
• Sometraitswithaplasticcomponent:intelligence,height,temperaturetolerance,salinitytolerance,musclemass…
PhenotypicPlasticity 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
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HebertandGrewe,1985
Predator induced formation of helmets in
Daphnia
Exampleofphenotypicplasticity,causedbyenvironmentalchange(notnecessarilyepigenetic)
(2)EpigeneticModifications
SomeTypesofEpigeneticmodifications(incompletelist)
• ChromatinModification: epigeneticalterationofchromatinstructure,affectinggeneexpression
Examples:MethylationHistone Modifications(acetylation,deacetylation)ChromatinRemodelling
• RNA-mediatedModifications: post-transcriptionalRNAmodifications
Examples:RNAinterference(RNAi)basedmechanism - RNAstrandsinterferewiththetranscriptionofDNAortranslationofmRNA
-- OftensmallRNAs,oftenthosethattargettransposableelements-- Seemstooccurmainlyatretrotransposons andotherrepeatedelements.
-- Genomicimprinting: wheremethylation andhistone modificationsaltergeneexpressionwithoutalteringthegeneticsequence.Wheninherited,these“epigeneticmarks”areestablishedinthegermlineandaremaintainedthroughoutallsomaticcellsofanorganism.
-- GeneSilencing:couldoccurthroughseveralmechanisms,suchashistonemodification,mRNAdestruction,orRNAinterference(RNAi).
-- Paramutation:whereinteractionbetweentwoallelesatasinglelocus,resultsinaheritablechangeinexpressionofoneallelethatisinducedbytheotherallele.Mechanismisnotfullyunderstood,butcouldoccurviamethylation orregulatoryRNAs.Paramutation violatesMendel’sfirstlaw,whichstatesthateachalleleremainscompletelyuninfluencedbytheother.
ConsequencesofEpigeneticModifications:ChangesinGeneExpression
Paramutations werefirstdiscoveredandstudiedinmaize(Zea mays)byR.A.BrinkattheUniversityofWisconsin–Madison(DeptofGenetics)inthe1950s
OriginalArticle:R.A.BrayandR.A.Brink.1966.MutationandParamutation attheRLocusinMaize.Genetics.54:137–149.
ChromatinModification
Portela &Esteller.2010.Epigeneticmodificationsandhumandisease.NatureBiotechnology 28:1057–1068
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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
Examples:
Epigenetic Modifications DNAMethylationEpigeneticmodifications
DNAmethyltransferases
• Additionofamethylgroup(CH3)atthe5positionofcytosineàreducegeneexpression
• Inadultsomatictissues,methylation usuallyoccursintheCpG islands,aCGrichregion,upstreamofthepromoterregion.
• Inembryonicstemcellsnon-CpGmethylation isprevalent(significantcytosine-5methylationatCpA andCpT;Ramsahoye2000).
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
Example of a type of Epigenetic Modification:
DNA Methylation
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DNAMethylationEpigeneticmodifications
DNAmethylation iscarriedoutbyagroupofenzymescalledDNAmethyltransferases.
TheseenzymesnotonlydeterminetheDNAmethylation patternsduringtheearlydevelopment,butarealsoresponsibleforcopyingthesepatternstothestrandsgeneratedfromDNAreplication.
DNAmethyltransferases
DNAMethylation• Crucialpartofnormalorganismaldevelopmentandcellulardifferentiationinhigherorganisms
• Altersgeneexpressionpatternincells• Suppressesexpressionofviralgenesandotherdeleteriouselementsthathavebeenincorporatedintothegenomeofthehostovertime
• Playsacrucialroleinthedevelopmentofnearlyalltypesofcancer(hypermethylation,whichrepressestranscriptionofthepromoterregionsoftumorsuppressorgenes)
• Mightbethemechanismforlearningandlongtermmemorystorage
Epigeneticmodifications One way in which DNA Methylation suppresses gene expression
• Methylation atthepromotersiteorupstreamofthepromoter
• Methylation ofnucleotidesinaregulatoryelement,suchasthepromoter, orupstreamofthepromoter,couldleadtochangesingeneexpression.
• Usually,suppressionofexpressionoccursduetointerferencewithbindingofthetranscriptionfactor.
• Typicallymoremethylation leadstogreatersuppressionofgeneexpression
transcriptionfactor
changeingeneexpression
genepromoter
genepromoter
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FactorsthatcouldaffectDNAMethylation
TheEnvironment:suchasdiettoxins,vitamins,stress,affection(licking,hugging),etc.etc…
• ExampleofDNAMethylation:DNAmethylationoftheagoutigeneinmicehavebeenfoundtocausebrownskinnymice…demethylation ofthisgene(increasedexpressionofagouti)resultsinyellowfatmice
• TheAgoutiviableyellow(Avy)alleleiscreatedbyaretrotransposon insertionofanelement(intracisternal Aparticle,IAP)upstreamoftheagoutilocus.
• DNAmethylation oftheIAPpromoteratAvy reducestranscriptionoftheAvy gene(getbrownskinnymice)
DNAMethylation:Childhoodtrauma
• EarlychildhoodtraumacanleadtoDNAdemethylation oftheFKBP5geneinhumanindividualsthatpossessparticularallelesatthisgene.
• FKBP5regulatesglucocorticoid receptoractivityandstressresponse.Demethylation ofthe“AA”genotypeleadstoexcessiveglucocorticoid receptoractivation.
• Thosehomozygousforthe“A”alleleoftheFKBP5geneweremorelikelytosufferfromdepression,post-traumaticstressdisorder,oranxietydisordersinadulthood,iftheywereabusedaschildren(causingdemethylation atthislocus).
http://usrexp-sandbox.nature.com/neuro/journal/v16/n1/full/nn.3275.htmlKlengel,T.etal.Allele-specificFKBP5 DNAdemethylation mediatesgene–childhoodtraumainteractions.NatureNeurosci.2Dec2012
Histone Modifications Histone Deacetylases/Histone Acetyltransferase
• Theabilityofaparticulartranscriptionfactortobindtoitstargetgeneis,inpart,dependentonmodificationsthataremadetothehistone proteins
• AbnormalactivityofHDACs hasbeenobservedinacutepromyelocytic leukemia,acutemyelogenous leukemia,non-Hodgkinlymphoma,andsometypesofcolorectalandgastriccarcinoma
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Histone Deacetylases/Histone Acetyltransferase
Histone Acetylation orDeacetylation:affectslevelofrelaxationofthechromatinandlevelofgenetranscription.
• Histone acetyltransferases (HATs): Acetylate Histones,enhancetranscription; acetylation neutralizespositivechargesonthehistone bychangingaminesintoamidesanddecreasestheabilityofthehistones tobindtoDNA,allowinggeneexpression
• Histone Deacetylases (HDACs): Deactylate Histones, represstranscription;removeacetylgroupsfromanε-N-acetyllysineaminoacidonahistone
Exampleofhistone deacetylase:Aging
• Sirtuin orSir2proteins areaclassofproteinsthatpossesseitherhistonedeacetylase ormono-ribosyltransferaseactivity.
• AsHistone Deacetylases,Sirtuins regulatetranscription• Sirtuins havebeenimplicatedininfluencingaging,stress
resistance,insulinsignalingandmetabolism(energyefficiency),andapoptosisandcancersuppression
• Caloricrestrictionà activatesirtuinsà slowdownaging• Drugsthatactivatesirtuins mightalsoslowdownaging
• Forexample,cooperateswithHIC1toregulateactivityofp53(tumorsuppressorgene)andapoptosis
SIRT1regulatesmanyfunctionsinvolvingapoptosisandcellsurvival
DNAMethylationandHistoneDeacetylation:Goodparenting(transgenerational epigeneticeffect)
• Increasedmaternalcareresultsintwotypesofepigeneticchanges:(1) acetylation ofhistones H3-K9,and(2) demethylationofthetranscriptionfactor(NGFI-A)bindingsitetothepromoteroftheglucocorticoid receptorà higherGRactivity
• Offspringthatreceivedhighlevelsoflicking/groomingshowlowerstressresponse(happyandcalm)andbecomegoodmothersthatlicktheirpupsalot…leadingtothesameepigeneticpatterns
• Thus,thebehavioroflickingresultsinthesameepigeneticpatternbeingpassedon
Inrats,mothersthatengageinhighorlowamountsoflicking/groomingoftheirpups
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
• Thisisanimportantexampletoillustratethedifferencebetweenatransgenerational epigeneticeffectversustransgenerational epigeneticinheritance
• Thisisatransgenerational epigeneticeffect(maternaleffect),butNOTtransgenerational epigeneticinheritance
• ***Thisis NOTEpigenetic Inheritance becausethebehaviorispassedon,ratherthantheepigeneticmarkitself...theepigeneticmarkisinducedbythebehavioroflickingateachgeneration
DNAMethylation andHistoneDeacetylation:Goodparenting (3)EpigeneticInheritance
• Onlythoseepigeneticmodificationsthatareheritableviathegametes(germline)à leadtoepigeneticinheritance.
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(3)EpigeneticInheritance• Mostepigeneticmodifications,i.e.epigeneticmarks,thatareestablishedinmosttissuesduringanorganism’slifetimeareirrelevantwithrespecttothenextgeneration.
«Thisisbecauseepigeneticmodificationsarenormallyerasedateachgeneration.Forexample,DNAmethylation istypicallyremoved(orpossiblyoxidized;Iqbal etal.2011)duringzygoteformationandre-establishedthroughsuccessivecelldivisionsduringdevelopment.
«Andalsobecauseonlyepigeneticmodificationsofthematuregametes(andnotinothertissues)havethepotentialtocontributetothephenotypeoftheoffspring,thenextgeneration.
• Onlythoseepigeneticmodificationsthatareheritableviathegametes(germline)à leadtoepigeneticinheritance.
EpigeneticInheritance
Alterationsingeneexpressionthatarepassedontothenextgeneration,butwheretheDNAitselfremainsunchanged
Stillanewfrontier(thisfieldisstillextremelynew),withmanyexamplesinplantsandfewerconcreteexamplesinanimals
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InthetoadflaxLinaria vulgaris,radially symmetricflowers,ratherthanthetypicalbilaterallysymmetricones,iscausedbyDNAmethylation oftheCYCLOIDEAgene,whichcontrolstheformationofdorsalpetals.
ExamplesofEpigeneticInheritance
FlowerSymmetry
• Sometomatoesdonotripenandremaingreen.
• Thesetomatoeshaveaheritablecytosinehypermethylation oftheCnr genepromoter,whichinhibitsexpressionoftheCnr gene
http://usrexp-sandbox.nature.com/nbt/journal/v31/n2/full/nbt.2497.html
ExamplesofEpigeneticInheritance
EpigeneticTriggerfortomatoripening
Hypermethylation oftheCnr promoterresultsininhibitionofRINtranscriptionfactorbinding,preventingCnr geneexpressionandfruitripening.
http://usrexp-sandbox.nature.com/nbt/journal/v31/n2/full/nbt.2497.html
• MethylationatFKBP5 geneinHolocaustsurvivorsandtheiroffspring.Thisgeneaffectsglucocorticoidresponse(stressresponse),andislinkedtoPTSDanddepression(RachelYehudaetal.2015)à needsmorestudy
• Resultsarenotclearlyinterpretable(http://blogs.plos.org/biologue/2015/07/07/human-disease-epigenomics-2-0/)
• Miceexposedtotoxinspassonfearoftheodorofthattoxinontotheiroffspring(not100%conclusive)
• ExamplesofEpigeneticInheritance aremuchmorecommoninplantsandmoreconclusive
PotentialExamplesofEpigeneticInheritance(notconclusive)
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http://www.scientificamerican.com/article/descendants-of-holocaust-survivors-have-altered-stress-hormones/
http://www.nature.com/news/searching-chromosomes-for-the-legacy-of-trauma-1.15369
http://www.biologicalpsychiatryjournal.com/article/S0006-3223%2815%2900652-6/abstract
References
http://www.nature.com/news/fearful-memories-haunt-mouse-descendants-1.14272
http://usrexp-sandbox.nature.com/nbt/journal/v31/n2/full/nbt.2497.html
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Whichchangesallelesfrequencies?Whichchangesgenotypefrequencies?
• Selection• GeneticDrift• Inbreeding• Recombination• Mutations• Migration(Geneflow)• Epigeneticmodifications