epigenetic

doi:10.1152/japplphysiol.00238.2010

109:586-597,ublished6May2010;JApplPhysiol

SusanaGonzalo

Epigeneticalterationsinaging

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HIGHLIGHTEDTOPICEpigeneticsinHealthandDia

Epigeneticalterationsinaging

SusanaGonzalo

RadiationandCancerBiologyDivision,DepartmentofRadiationOncology,andDepartmentofCellBiologyandPhysiology,

WashingtonUniversitySchoolofMedicine,,Missouri

Submitted4March2010;acceptedinfinalform3May2010

hysiol109:586–597,2010.

FirstpublishedMay6,2010;doi:10.1152/japplphysiol.00238.2010.—Agingisa

multifacetedprocesscharacterizedbygeneticandepigeneticchangesinthe

eticcomponentofagingreceivedinitiallyalloftheattention.

Telomereattritionandaccumulationofmutationsduetoaprogressivedeficiencyin

therepairofDNAdamagewithageremainleadingcausofgenomicinstability.

However,epigeneticmechanismshavenowemergedaskeycontributorstothe

ee

pillarsofepigeneticregulationareDNAmethylation,histonemodifications,and

tionsoftheepigeneticmechanismsaffectthevast

majorityofnuclearprocess,includinggenetranscriptionandsilencing,DNA

replicationandrepair,cellcycleprogression,andtelomereandcentromerestruc-

,wesummarizethelinesofevidenceindicatingthatthe

epigeneticdefectsmightreprentamajorfactorinthepathophysiologyofaging

andaging-relateddias,especiallycancer.

cancer;epigeneticchanges

ANEWCONSENSUSFORTHEDEFINITIONofepigeneticshasrecently

beenreached:“Anepigenetictraitisastablyheritablepheno-

typeresultingfromchangesinachromosomewithoutalter-

ationsintheDNAquence”(8).Acascadeofsignaling

events,activatedbyanenvironmentalcuereferredtoas“epi-

genator”,isrequiredtoeffectthechromosomalchanges.

Next,an“epigeneticinitiator”establishestheregionofthe

chromosomethatwillundergoepigeneticregulation,andan

“epigeneticmaintainer”executestheepigeneticmodifications

thatchangechromatinstructure(8).Themainplayersthat

orchestratechromatinregulationareDNAmethylation,histone

modifications,ivecrosstalkamong

theplayersregulatesgeneexpressionandmaintainsfaculta-

ishmentofdiffer-

entcombinationsofchromatinmarkstscodesthatcanbe

readbychromatin-associatingcomplexes(58,59,66,118).

Thecomplexes,inturn,executeadditionalchromatinmod-

ificationsand/orrecruiteffectorsthatregulatethespecific

biologicalprocess:transcription,DNAreplicationandrepair,

celldivision,andcentromereandtelomerefunction,among

others(7,9,15,46,103).Compellingevidenceindicatesthatthe

combinationofgeneticandepigeneticalterationscontributesto

humandia,includingneurologicalandcardiovasculardis-

eas,autoimmunedisorders,cancer,calter-

ations,suchasmutations,deletions,andtranslocationsortelomere

loss,areamongtheleadingcausofgenomicinstabilityinaging

bodyofevidenceindicatesthatepigenetic

alterationsalsocontributetoaging-associatedpathologies,espe-

eticchangesmayinitiateagingandcancer

phenotypes,orprimecells,insuchawayastomakethemmore

accumulationoffurthergeneticorepigeneticchangesovertime

wouldpromotetheprogressionofagingandcancerphenotypes

(Fig.1).

EPIGENETICMECHANISMS:DNAMETHYLATION,HISTONE

MODIFICATIONS,ANDNONCODINGRNAs

Thebasicunitofchromatin,thenucleosome,consistsof

DNAthatwrapsaroundanoctamerofhistones(78)(Fig.2A).

Manydifferentcellularactivitiestargetthenucleosomeasto

modulatechromatinstructure,eitheratspecificgenomicloci,

oratlargechromosomaldomains(115).Thehistonetails

protrudefromthenucleosomecoreandaresubjectedtodif-

ferentposttranslationalmodifications(59).Anextremelycom-

plicatedpicturehamergedaboutthetypesofposttransla-

tionalmodificationsofhistonesandtheenzymaticactivities

responsibleforthemodifications(64,66,83).Histonemod-

ificationsincluderineandthreoninephosphorylation,lysine

acetylation,lysineandargininemethylation,ADP-ribosylation

ofglutamicacids,lysinesumoylationandubiquitylation,and

prolineisomerization(Fig.2B).Themainpurpoofthe

histonemodificationsistoprentaplatformforbindingofa

varietyofchromatinassociating/remodelingactivitiesthat,in

turn,alloworrestricttheaccessofregulatoryproteinstoDNA.

Addressforreprintrequestsandothercorrespondence:o,Radia-

tionandCancerBiologyDivision,ationOncology,Washington

ofMedicine,4511ForestPark,,MO63108(e-mail:

sgonzalo@).

JApplPhysiol109:586–597,2010.

FirstpublishedMay6,2010;doi:10.1152/

8750-7587/10Copyright©2010theAmericanPhysiologicalSociety586

atSouthUnivofSciandTechofChinaonApril10,2013/

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MethylationofnucleosomalDNAbyDNAmethyltrans-

feraactivities(DNMTs)istablishedasameanstomodu-

latethetranscriptionalactivationorrepressionofmanygenes.

DNAmethylationconsistsoftheadditionofamethylgroupto

efoundatlow

frequencyinthegenome,butaccumulateatspecificgene

promoters,CpGislands(11,65).ThebulkofDNAmethyl-

ationisfoundatrepetitivequences,suchastransposonsand

ationofrepet-

itivequencespreventsrecombinationortranslocation

throughoutthegenome(20).

Thetypesofposttranslationalmodificationsofhistonesand

thedegreeofDNAmethylationdetermineaspecificchromatin

structure(71,135).Ineukaryotes,twomorphologicallydistinct

typesofchromatincanbedistinguished,namelyeuchromatin

andheterochromatin(28,39)(Fig.2C).Euchromatinisasso-

ciatedwithgene-richandtranscriptionallyactivedomainsof

disperdappearance,characterizedbiochemicallybyhyper-

acetylationofhistonesandhypomethylationofbothhistones

rast,highlycondendheterochromatinis

linkedtogene-poorandtranscriptionallyinactivedomains,

mically,heterochro-

matinischaracterizedbyhypoacetylationofhistonesand

hypermethylationofhistonesandDNA(44,82).However,

thetwomorphologicallydistinctchromatindomainscanalso

mple,euchromaticpromoters

asmbleabatteryofchromatin-modifyingactivitiesthatin-

ducealocalclosingofchromatinaroundthepromotersuffi-

odchromatinstate

aroundthepromotersharesmanysimilaritieswiththemech-

anismofglobalheterochromaticsilencing(42).

WhilehistonemodificationsandDNAmethylationhave

beenrecognizedascanonicalepigeneticmodifications,non-

codingRNAs(ncRNAs)havebeenrecentlyrecognizedas

playersinchromatinremodeling,primarilyinvolvedinhetero-

chromatinformationandtranscriptionalorposttranscriptional

ajorspeciesofncRNAshavebeen

identifiedinmammaliancells:1)smallinterferingRNAs

(siRNAs),moleculesof21–25nucleotidesoriginatedfrom

double-strandedRNAthataretargetedtochromatinandpar-

ticipateingenesilencingandintheasmblyofheterochro-

maticdomains(85);2)micro-RNAs(miRNAs),generated

fromindividualRNAmoleculesthatformhairpinstructures,

induceposttranscriptionalsilencingbyinhibitingtranslation

(50);3)Piwi-associatedRNAs,moleculesof28–33nucleo-

tidesfunctioninpreventingthemobilityoftransposons(3).

TheroleofncRNAsingenomefunctionandintegrityisonly

beginningtobeunraveled.

DNAMETHYLATION

DNAmethylationisoneofthebestunderstoodmodifica-

tionsofchromatin,withcrucialrolesingeneexpressionand

imprinting,defenagainstviralquences,inhibitionofre-

combination,aswellasasmblyofheterochromatin(11).

ThreeactiveDNMTactivities(DNMT1,DNMT3a,and

DNMT3b)havebeenidentifiedinhumansandmice(93,94)

(Fig.3).DNMT1functionsprimarilyasmaintenanceDNMT,

responsibleforcopyingtheparental-strandDNAmethylation

patternontothedaughterstrandaftereachroundofDNA

3aandDNMT3bfunctionasdenovo

DNMTs,althoughtheycanalsomaintainmethylationpatterns.

DNAmethylationisassociatedwiththeinductionofaclod

chromatinstatebyrecruitmentofproteincomplexesthatbear

repressivechromatinmodifyingactivities,includingMBD

(methyl-CpG-bindingdomain)proteinsandhistonedeacety-

la(HDAC)-containingcomplexes(4,65).Cytosinemethyl-

ationateuchromaticpromotersparticipatesinswitchingoffthe

rochromaticdomains,itpartici-

patesintheasmblyofthehighlycompactedchromatin

ntDNAmethylation

fhowgeneticandepigeneticalterations

candepigenetic

alterationscontributetowardthepathogenesisofaging

andaging-relateddias,c

alterations,suchaschromosomaldeletions,DNArear-

rangements,geneamplifications,andmutations,can

eticalter-

ations,includingchangesinDNAmethylation,histone

modifications,andlevelsofexpressionofnoncoding

RNAs,etic

changesmaydirectlytriggeragingandcancerpheno-

types,orprimecellstomakethemmoresusceptibleto

subquentgeneticorepigeneticalterations.

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patternshavebeenlinkedtogenomicinstabilityandincread

mutationrates,hallmarksofdia,especiallycancer(23,74).

Ground-breakingstudiesperformedinratbrainandheart

showedagloballossofDNAmethylationduringaging(127),

whichwaslaterconfirmedindifferenttissuesfromrat,mou,

andcow(102),inprimaryfibroblastsfrommice,hamsters,and

humansgrowninculture(134),andinhumanlymphocytes

(29)andperipheralbloodcells(14,38).Paradoxically,a

varietyofspecificlocibecomehypermethylatedinnormal

tissuesduringaging(35).AstudyusingT-lymphocytesiso-

latedfromindividualsofdifferentages,rangingfromnew-

bornstoelderlypeople,showedhypermethylationofϳ1%of

ablechangesin

DNAmethylationatthelociwereobrvedinothertissues

(124).Similarly,astudyofchangesinDNAmethylationinthe

humancerebralcortexidentifiedamarkedincreaincytosine

methylationat8outof50lociexamined(114).Specific

examplesofgenesthatarehypermethylatedduringaging

includetheestrogenreceptor(ER)(55),insulin-likegrowth

factor-II(IGF-II)(56);p14ARF(110);p16ink4a(116),E-cad-

herin(17),c-fos(24),andcollagen-␣1(121).Interestingly,

manyofthepromotersarealsohypermethylatedduring

tumorigenesis,suggestingaroleintheincreadcancersus-

ceptibilityassociatedwithaging.

leosome,chromatin,andspecificmarks.

A:diagramofanucleosome,formedbyanoctamerofhistones

etailsprotrudingfromthe

nucleosomecoreareshownwithavarietyofposttranslational

modifihylationandbindingofnoncoding

RNAs(ncRNAs)arealsoshown.B:thefourhistonetailsare

shownwiththecorrespondingposttranslationalmodifications

atspecificresidues.C:diagramillustratingthedifferences

-

matinischaracterizedbyhyperacetylationofhistonesand

rast,hetero-

chromatinshowshypoacetylationofhistonesandhypermeth-

ylationofhistonesandDNA.

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Thedifferentlinesofevidenceindicatethataglobal

hypomethylationofthegenomeaccompaniestheagingpro-

cess,concomitantwithincreadmethylationofspecificgene

promoters(19,32)(Fig.3).Themolecularmechanismsbehind

thechangesinDNAmethylationpatternsduringagingre-

riptionalcontrolofDNMTswasshown

tobealteredinagedandtransformedhumanfibroblasts(21).

Infact,itwaspropodthattheglobaldecreainDNA

methylationcouldstemfromaprogressivedecreainthe

efficacyofDNMT1activityonheterochromaticdomainsdur-

ingaging(21,35).Incontrast,thehypermethylationofspecific

promoterCpGislandscouldbebroughtaboutbyoverexpres-

icular,upregulationof

DNMT3bwasreportedinculturedfibroblasts(21,35).Future

studiesneedtodeterminewhethertranscriptionalchangesare

indeedresponsiblefortheaccumulationofDNAmethylation

alterationsduringaging,andwhetherthechangesincrea

cancersusceptibilitywithage.

HISTONEACETYLATION/DEACETYLATION

Histoneacetyltransferas(HAT)andHDACmodulatethe

additionorremovalofacetylgroupsonhistones,asmeansto

regulatetranscription(7)(Fig.4).Acetylatedlysineresidues

rveasbindingplatformsforproteinsthatcontainthebromo-

domainproteinmodule,foundinsometranscriptionfactors,as

ferent

proteinsplayingaroleinDNAmethylationareshownwith

theirreportedmolecularactivityandcellularfunction.A

summaryofthechangesobrvedinDNAmethylation

patternsduringcancerandagingbydifferentstudiesare

angesatagloballevelandatspecific

,estrogenreceptor;

BRCA1,breastcancer1;APC,adenomatosispolyposis

coli.

e-modifyingactivitiesinaging

gofthemajorclassof

histone-modifyingactivitiesindicatetheirspe-

cificactivitiesandreportedcellularfunction.

HDACs,histonedeacetylas;HATs,histone

acetyltransferas;HMTs,histonemethyltrans-

aofHMTs,thespecificlysine

residuesthataremethylatedandtheirfunction

ryofthechangesob-

rvedinhistonesmodificationsduringaging

atthechanges

inSIRT1expressionandH4K20me3levelsdur-

ingagingandcancergointheoppositedirec-

tfordefinitionofhistoneacronyms.

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wellasinsubunitsofchromatin-remodelingcomplexes(27,

49,57).HATactivitiesareusuallyfoundinlargemultisubunit

l,acetylationoflysineresiduesonhistones

isassociatedwithtranscriptionalactivationandDNArepair

(47,69).Converly,histonedeacetylationallowstheacquisi-

zymesdeacetylate

allfourhistonesandcanactonnonhistonesubstratesaswell.

Overall,histonedeacetylationisassociatedwithchromatin

recondensation,transcriptionalrepression,andasmblyof

heterochromatin.

HDACactivities,suchastheyeastHDACSir2(silent

informationregulator2),anditsfunctionalmammalianor-

thologs,thesirtuins,arethebestexampleofanepigenetic

rstudiesbyBrian

Kennedyandcolleagues(62)demonstratedaclearcorrelation

betweenexpressionofproteinsoftheSircomplex,Sir2/Sir3/

Sir4,onofSir4abolishedsilenc-

ingofyeast-matinglociandtelomeresandcaudadecreain

rast,again-of-functionmutationinSir4in-

ducedtherelocationoftheSircomplexfrommatinglociand

telomerestothenucleolusandextendedlifespanby30%(63).

Furthermore,increadSir2activityhasanti-agingeffectsin

yeast(61),s(123),gaster(101).

Interestingly,theclostmammalianorthologofSir2,SIRT1,

1deacetylateshis-

toneH4atlysine16(H4K16)andhistoneH3atlysine9

(H3K9)positions(99,129)anddeacetylatesalsop53,decreas-

neinthelevelsofSIRT1proteinwas

obrvedconcomitantwithdecreadmitoticactivityinmou

decreaswereespeciallyfound

duringagingorinprematureagingmice(Fig.4).Incontrast,

SIRT1increaswhencellsarestimulatedtodivideinvitro,

andupregulationofSIRT1isahallmarkofawholespectrum

ingly,lossofH4K16acetylationwas

identifiedasacommoneventinhumancancer(34).Thedata

suggestthatthe“downregulationofSIRT1duringagingmight

reprentatumor-suppressormechanismthatstabilizesp53at

tyof

molecularmechanismscouldbebehindSIRT1functionin

1canregulategene

expression(92,98,99),formationoffacultativeandconstitu-

tiveheterochromatin(128,129),signalingthroughtheDNA

damageresponpathway(80,130),andDNAmethylation

patterns(90).Thusitistemptingtospeculatethataprofound

decreainthelevelsofSIRT1duringagingcouldincrea

nleadtodecreadcellviability,

egulation

ofSIRT1duringthetransformationofnormalcellstomalig-

nantderivativescouldpromotethelongevityofthetrans-

tthatincreadSIRT1expressionpro-

motedsurvivalinamoumodelofgenomicinstability(91)

supportsthismodel.

SIRT6,anothermemberofthesirtuinsfamily,hasbeen

showntoberequiredforDNArepairandgenomicintegrity.

Accordingly,SIRT6deficiencyleadstoadegenerativeaging-

likephenotypeinmice,includinggrowthretardation,lym-

phopenia,lossofsubcutaneousfat,lordokyphosis,andvere

metabolicdefects,dyingataround4wkofage(87).Overall,

thestudiesprovideevidenceofsirtuinsplayingaroleinthe

pathophysiologyofagingandcancer,makingtheproteins

,recentstudieshave

shownthatinhibitorsofsirtuinxhibitstrongcancer-specific

proapoptoticeffects(72).Itisimportanttonotethat,despiteall

thatwehavelearnedaboutsirtuinfunctionincancerandaging,

therolethatmostHATsandHDACsplayintheprocess

remainsunknown.

HISTONEMETHYLATION/DEMETHYLATION

Histonemethylationplaysanimportantroleintranscrip-

tionalregulationandintheasmblyoffacultativeandcon-

stitutiveheterochromatin(70,84,105,112,115).Histone

methyltransferas(HMTs)aretheenzymesresponsibleforthe

transferofmethylgroupstolysineorarginineresidueson

histonesH3andH4(Fig.4).Lysines4,9,27,36,and79onH3

ationof

lysineresiduescanhavetranscriptionalrepressiveoractivating

effectsonchromatin,dependingontheparticularlysinethat

thylationofH3K9,H3K27,

andH4K20isgenerallyassociatedwithtranscriptionalrepression,

whilemethylationofH3K4(H3K4me3),H3K36(H3K36me3),and

H3K79isassociatedwithactivechromatin(67).Genomewide

chromatin-statemapsofstem,progenitor,ordifferentiated

cellshaveshownthatH3K4me3andH3K27me3discriminate

genespoidfortranscriptionalactivationorrepression,re-

3K36me3markssitesoftranscriptionof

codingandncRNAs,H3K9me3,andH4K20me3markhetero-

chromaticdomains,suchaspericentricandtelomericchroma-

tin(86).

Anotherlevelofcomplexityinthehistonecodeisthefact

thatlysineresiduescanundergomono-,di-,ortrimethylation,

eachprovidingaspecificdegreeofchromatincompactionand

adifferentbindingplatform(137).Asforlysineacetylation,

methylationoflysineresiduesinhistonescreatesbindingsites

forchromodomain-containingproteins;suchisthecaof

H3K9methylation,bindingsiteforHP1(heterochromatin

protein1),andH3K27methylation,bindingsiteforpolycomb

proteins(137).RecruitmentofHP1isimportantforthemain-

tenanceofheterochromatindomains,andoccupancyofgene

promotersbypolycombcomplexesfavorsanenvironmentfor

edemethylationhasalsobeen

describedandisbelievedtoantagonizethefunctionoflysine

methylationindiverbiologicalprocess(65,111,126,133,

136).

Changesinhistonemethylationpatternshavebeenobrved

duringaging(Fig.4).Earlystudiesinratsshowedthatmeth-

ylationofhistonesH3andH4declinesgraduallywithincreas-

ingage(122).Asystemicinvestigationofposttranslational

modificationsofhistonesinthebrainofnescence-acceler-

atedpronemou8(SAMP8)modelhasrevealedanumberof

changesduringaging(132).Sevenmethylationsiteswere

e,

H4K20me(H3monomethylatedonlysine20)andH3K36me3

(H3trimethylatedonlysine36)decreadsignificantlyinthe

brainof12-mo-oldSAMP8micecomparedwith3-mo-old

rast,theabundanceofH3K27me3,H3K79me,

her

studyperformedinkidneysandliverofagedrats,thelevelsof

mono-anddimethylatedH4K20didnotsignificantlyvarywith

ly,H4K20me3wasgreatlyincreadduring

aginginthetissues(106).Similarly,thelevelsofH4K20me3

increainnescentcells(35).Thishistonemarkisstabilized

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bythecoordinatedactionofHMTsSuv4–20h1andSuv4–

20h2andtheretinoblastomafamilyofproteins(pRb,p107,and

p130)(6,43).Thusalterationsintheexpressionofthe

proteinsorintheiractivitiesduringagingcouldbebehind

H4K20me3changes.

Changesinhistonemodificationsatspecificgenomicloci

mple,

polycombproteinsandassociatedrepressiveepigenetic

marksregulatereplicationtimingandsilencingoftheink4a/

ARFlocus(1).Inyoungcells,thepolycombrepressive

complex(PRC2)memberEZH2(enhancerofzestehomolog

2)andmembersofthePRC1complexBmi1(B-cell-specific

Moloneymurineleukemiavirusintegrationsite1)andM33

arehighlyexpresdandtargetedtotheink4a/ARFlocus.

Thisresultsinsilencingofthelocusandreplicationduring

tryintonescence,PRC1andPRC2

complexesarelostatthislocus,leadingtodecread

itantly,upregulationofthehis-

tonedemethylajumonjidomaincontaining3andrecruit-

mentofthemixedlineageleukemiagene1proteintothe

locusresultsinexpressionoftheink4a/ARFgenesand

tudies

showthatchangesintheepigeneticstatusofspecificloci

canplayakeyroleduringnescence.

Overall,changesinthemethylationstatusofhistone

-

ever,thesignificanceofthefindingsforthepathophysi-

hat

histonemethylation/demethylationcanregulatetranscrip-

tionalactivationorrepression,onecananticipatethat

changesinthismarkcanswitchon/offmanygenesthat

collectivelypromoteagingoraging-associateddias,

rmore,theroleofmethylationof

certainhistoneresiduesonDNArepairandmaintenanceof

heterochromatindomains,suchastelomeresandcentro-

meres,suggeststhatapropertofhistonemethylation

markscouldhelppreventgenomicinstability.

EXPRESSIONOFmiRNAs

TherolesofncRNAspeciesingenomefunctionand

t

varietyof

functionshavebeenattributedtomiRNAs,includingcell

cycleregulation,differentiation,apoptosis,andtumorsup-

pression(45)(Fig.5).Ithasbeenestimatedthatasingle

miRNAcanhavehundredsoftargets,illustratingthecom-

miRNAsnegativelyregulategeneexpressionbyeitherde-

gradingtargetmesngerRNAsorinhibitingtheirtransla-

tion(50,75).Ithasbeenpropodthatϳ60%ofhuman

genesarecontrolledbyanevergrowinglistofmiRNAs(5,

37).Recentgenomewideanalyshaveshownthat95%of

thehumangenomeistranscribed,andthatthevastmajority

oftranscriptsarenoncoding(13,131).Interestingly,epige-

neticmechanismscanmodulatetheexpressionofmiRNA

(104),andmiRNAscanimpactonthelevelsofchromatin-

modifyingactivities,suchasDNMTsandHMTs(33,36).

ThefirstevidenceaboutamiRNA-regulatinglifespan

s(73).ThemiRNAlin-4was

showntoregulatetheproteinlin-14,anesntialtranscrip-

tionfactorthataffectsavarietyofsignalingpathways

controllingdevelopmentaltimingandlifespan(16,54).The

increainlongevityonupregulationoflin-4appearstobe

mediatedbytheinsulin/hen,a

varietyofmiRNAsthatmodulatedifferentplayersinthispath-

wayinmammaliancellshavebeenidentified(45).Future

studiesneedtodeterminewhetherthemiRNAshavea

ewreportshave

shownacorrelationbetweenchangesinmiRNAexpression

andaging(75).Inliver,forexample,arrayprofilingofglobal

miRNAexpressionshowedupregulationofmiRNAsduring

aging(81).

Theaccumulationofgenomicinstabilityisconsideredakey

stingly,anumberofmiRNAs

areinducedinrespontocellularstress,leadingtodecread

levelsofproteinsinvolvedinDNArepair(22).Inparticular,

thehypoxia-induciblefactor-1␣(HIF-1␣)activatesmiRNAs

(100,120).Importantly,hypoxia-inducedmiRNAsareover-

expresdinsomehumantumors,suggestingaroleforthe

ncRNAsintheincreadsusceptibilitytocancerduringaging

(68).Furthermore,p53isupregulatedinrespontoanumber

uingly,p53regulatestheexpression

ofmiRNAswhilebeinganindirecttargetofmiRNAaction

(51,95).Theregulationofp53bymiRNAsplacesthe

ncRNAsatacentralpositioninthecontrolofgenomicstabil-

ity.

ingRNAs[micro-RNAs(miRNAs)]inaging

yisgivenofsomeofthefunctions

reportedformiRNAsandchangesthatcouldhaveanimpactin

cancerandagingphenotypes.

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EPIGENETICALTERATIONSINCANCER

Theevidencetodatesuggeststhatagingisassociatedwith

r,howthiscontributes

ep-

tionistheclearconnectionthathasbeenestablishedbetween

hat

agingreprentsthehighestriskfactorforcancer,itisconsid-

eredthatcancersusceptibilityincreasascellsaccumulate

mutationsandepigeneticalterationsduringaging,which,in

turn,provideproliferativeadvantagesandincreadgenomic

instability(Fig.1).

CancerischaracterizedbyglobalDNAhypomethylation

andsite-specificpromoterhypermethylation(32,60)(Fig.3).

DNAhypomethylationinitiateschromosomeinstabilityand

activatesprotooncogenes,increasingtumorfrequencyin

moumodels(30,53).CpGislandslocatedingenepromoters

areunmethylatedinnormaltissues(12).Denovomethylation

oftheislandsoccursinavarietyoftumors,leadingto

thefirstlinksbetweenCpGislandmethylation,genesilencing,

andtumorigenesiswasprovidedbystudieswiththeERgene.

MethylationoftheERgeneCpGislandwasshowntoincrea

innormalcolonicmucosaasafunctionofageandbeprent

incolonictumors(55).Interestingly,inculturedcoloncancer

cells,methylation-inducedsilencingoftheERgeneleadsto

increadgrowth,andexpressionofexogenousERresultsin

enesmodulatedbyhyper-

methylationinthistissuearetheN33andMYODgenes(2).

Thesamegroupofinvestigatorsalsoshowedalterationsin

DNAmethylationpatternsintheimprintedgeneforIGF-IIin

humantumors,includingcolon,breast,lung,andleukemias

(56).Classicaltumorsuppressorgenessuchasretinoblastoma,

p16ink4a,breastcancer1,adenomatosispolyposiscoli,von

Hippel-Lindau,andE-cadherinarealsosilencedbymethyl-

ationduringtumorigenesis(32).Thusincreadgenesilencing

bymethylationhamergedasaleadingcauoftumorigen-

esis.

Alterationsofhistonemodificationsarealsoahallmarkof

cancercells(109)(Fig.4).Inparticular,globaldecreasin

H4K16ac(34)andincreadlevelsofHDACsareoftenfound

incancercells(48,117).Thechangesinhistoneacetylation

contrast,thedecreadlevelsofH4K20me3(34)and

H3K9me3(88)obrvedinhumantumorscouldinduce

genomicinstabilitybyimpactingonthestructureofhetero-

chromatinorprovideaproliferativeadvantagebyaltering

telomeremetabolism(42,43).Importantly,acomparative

studyofcancercellsreprentingdifferentstagesofhuman

breastcancerrevealedthatthemoremalignantcellxhibited

thehighestdecreainH4K20me3levels(125).Thedecrea

inH4K20me3wasconcomitantwithlowerexpressionof

Suv4–20h2,suggestingthatthinzymemightregulatethis

histonemodifistingly,themoremalig-

nantcellsalsohaveamoreprominentlossofDNAmethyl-

ation,whichisaccompaniedbyalteredexpressionofDNMT1

esults

correlatemalignantprogressionwithmoreextensiveepigenetic

udiesareneededtoclearlydeterminethe

functionalinterplaybetweenspecificalterationsofDNAmeth-

ylationandhistonemodificationsandthecancerphenotype.

SeveralreportsindicatethatexpressionofmiRNAsisal-

teredduringmalignancy(Fig.5).Infact,miRNAexpression

profilesclassifyhumancancers(77).Theauthorsfoundthat

addition,ageneraldownregulationofmiRNAswasobrved

intumorscomparedwiththecorrespondingnormaltissues.

Furthermore,theprofilingexperimentsrevealedthatmiRNAs

l,thestudiessup-

portthenotionthatchangesinmiRNAexpressionarelinkedto

icular,miRNAscanactastumorsup-

pressors,es

ofmiRNAswithtumor-suppressivefunctionsaremiR15and

miR16,whicharelocatedinaregionthatislostinthemajority

ofchroniclymphocyticleukemias(18).Interestingly,are-

centlyidentifiedmoleculartargetofmiR15andmiR16is

Bmi1,agenethatisupregulatedinavarietyofepithelial

gulationofmiR15andmiR16inovarian

canceriscorrelatedwithBmi1proteinexpression(10).How-

ever,-17–92

clusterofmiRNAscooperateswithc-myctopromotetumor

icular,anupregulationofmiRNAsde-

rivedfromthislocusissubstantiallyincreadinB-celllym-

rmore,enforcedexpressionofmiR-17–92clus-

terandc-mycacceleratedtumorprogressioninamoumodel

ofB-celllymphoma(52).Anotherstudyshowedthatmyc

bindsdirectlytothemiR-17–92locusandactivatexpression

ofthemiRNAcluster(89).Atthesametime,miRNAsfrom

thisclusterwereshowntoinhibittheexpressionofthetran-

ntyears,manymoremiRNAs

havebeenidentifiedwhoexpressionisassociatedwithcan-

cer(25,79).SomeofthemiRNAsactastumorsuppressors

andaredownregulatedintumors,whileothersactasonco-

genesandareupregulatedincancer.

Insummary,thestudiesrevealedthatavarietyofpro-

cesscontributingtotumorigenesis,activationofoncogenes,

silencingoftumorsuppressorgenes,cellcycledefects,and

increadgenomicinstability,aresubjectedtoepigeneticde-

tandinghowepigeneticalterationscontrib-

utetohumancancerisanactiveareaofrearch,withhigh

potentialfortherapeutics.

EPIGENETICALTERATIONSINPREMATUREAGING

Prematureagingsyndromeshavebeeninstrumentalinthe

characterizationofmolecularmechanismsthatcontributeto

hemostdevastatingsyndromesof

prematureaginginhumansisHutchinsonGilfordProgeria

Syndrome(HGPS).PatientswithHGPSappearnormalatbirth,

butdevelopveregrowthabnormalitiesby2yrofage.

Childrenwithprogeriacontinuetoexhibitcharacteristicsas-

sociatedwithagingandgenerallydieduetoatherosclerosisin

caudbyamutationinthegeneencoding

A-typelamins,laminsAandC,structuralcomponentsofthe

nuclearlaminaandtheinnernuclearmatrix(26,31).The

mutationintheLMNAgeneassociatedwithprogerialeadsto

theexpressionofatruncatedformoflaminAknownas

progerin,stingly,normal

humanfibroblastsfromagedindividualsalsoexpressprogerin,

linkingalterationsofA-typelaminstophysiologicalaging

(107,108).Atthecellularlevel,commondefectsinHGPS

includeultrastructuraldefectsofthenuclearenvelope,lossof

Review

592EPIGENETICALTERATIONSINAGING

JApplPhysiol•VOL109•AUGUST2010•

atSouthUnivofSciandTechofChinaonApril10,2013/

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heterochromatinfromthenuclearperiphery(97,119),in-

creadgenomicinstability(76),andalterationsinepigenetic

markscharacteristicofconstitutiveheterochromatin(113).In

particular,decreadlevelsofH3K9me3atpericentrichetero-

chromatinanddecreadbindingofHP1tothedomains

wereobrvedinfition,

theauthorsshowedthatprogericfibroblastxhibitde-

creadlevelsofH3K27me3,concomitantwithdecread

levelsofEZH2,theHMTresponsibleforestablishingthis

rmore,anincreainH4K20me3levels

tstudyhasprovideda

mechanismresponsibleforthedecreainH3K9me3levels

efectswerelinkedtoareductionof

NURD(nucleosomeremodelingandhistonedeacetylation)

complexsubunits,specificallyRBBP4(retinoblastomabinding

protein4),RBBP7(retinoblastomabindingprotein7),and

HDAC1,whichinteractwithlaminA(96).Theauthorsfound

thatthelossofNURDsubunitsinHGPScellswasdependent

ether,thestudiessupport

thenotionthatdefectsinthestructuralnuclearproteinsA-type

laminsthatoccurinagingimpactonepigeneticmechanisms.

FurthersupportforaroleofA-typelaminsinepigenetic

regulationisthefactthatabrogationofA-typelaminsinthe

LmnaϪ/Ϫmoumodelinducesyetadifferentpatternof

changesinchromatinstructure(40,41).Fibroblastsfromthe

miceexhibitamarkeddecreainthelevelsofH4K20me3,

whilemaintainingthelevelsofH3K9me3,bothatpericentric

comitantdecreaof

retinoblastomafamilymembersobrvedinthecellsislikely

-typelamins

-

pressionofthemutantprogerinproteinleadstodefectsin

histonesmarkscharacteristicofphysiologicalaging,whileloss

ofA-typelaminsrecapitulatesphenotypesofcancercells.

SUMMARY

Awholebodyofevidenceindicatesthatalterationsinthe

threemajorepigeneticmechanisms,DNAmethylation,histone

modifications,andncRNAs,areahallmarkofagingand

lterationscanimpactlargechromosomaldo-

mainsorspecifi

maincellularconquencesofepigeneticderegulationare

changesinthetranscriptionalactivationandrepressionof

manygenes,anincreaingenomicinstability,andstructural

hevarietyof

cellularprocessthatareaffectedbyepigeneticmechanisms,

ithasbeenpropodthatepigeneticalterationscouldreprent

animportantfactorinpathophysiologyofagingandaging-

relateddias,stingly,someepige-

neticalterationsarecommoninagingandcancer,suggesting

thattheaccumulationofepigeneticdefectswithagemight

promotecellulartransformationandincreacancersuscepti-

thecaofglobalDNAhypomethylationand

rast,otherepigeneticalter-

ationsaremodulatedinanoppositewayinagingandcancer.

ThebestexamplesareH4K20me3levelsandexpressionof

elsofH4K20me3increaduringnormalaging

andinprogeria,-

larly,SIRT1isdownregulatedduringagingandupregulatedin

atasuggestthatthetransformationofnormal

cellstomalignantderivativesmightbeaccompaniedbyan

challengeinthefieldistoidentifythemolecularmechanisms

responsibleforthisswitch,whichcouldputativelyactas

llrequireestablishingthe

epigeneticsignatureofyoungandoldcells,aswellasnormal

-throughputmethodsneedtobecon-

ductedfortheconcomitantanalysisofanelevatednumberof

epigeneticmodifications,includingDNAmethylation,histones

modifications,ypesof

studies,incombinationwithgenomewideexpressionprofiles,

willbefundamentalfordetermininghowepigeneticchanges

findingshave

thepotentialtoimpactcellulardiagnosisforcancerscreening

andacceleratedrugdiscovery.

DISCLOSURES

Noconflictsofinterest,financialorotherwi,aredeclaredbytheauthor(s).

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