Download Epigenetic Inheritance - Carol Eunmi LEE

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