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DNAnotnecessarilyyourdestiny?Theroleofepigeneticsinpharmacy|News|PharmaceuticalJournal

DNAnotnecessarilyyourdestiny?Theroleofepigeneticsin
pharmacy
ThePharmaceuticalJournal,8JAN2013

Our2013scienceserieswilllookatthenewpharmaceuticalsciencesthat
areemerging.KalliopiDodouandPaulWhiteleyintroduceepigeneticsin
thisfirstarticle
Our2013scienceserieswilllookatthenewpharmaceuticalsciencesthatareemerging.KalliopiDodouand
PaulWhiteleyintroduceepigeneticsinthisfirstarticle
Inthecurrenteraofgenomics,whichcarriesthepromiseofpersonalisedmedicine,interestisalsogrowingin
theepigenomeandhowyourDNAmightnotnecessarilybeyourdestiny.
Sowhatisepigenetics?TheHongerwinter(hungerwinter)of1944inNazioccupiedNetherlandsaffectedover
fourmillionpeople.ItwasascribedtoacombinationofNazirevengeforthereluctanceoftheDutchpeopleto
aidtheAxiswareffortsandanunusuallyharshwinter:humankindandnaturejoinedforcestoinflictimmense
suffering.
Amongsuchdarkness,theexperiencesoftheDutchfamineofferedsciencesomepotentiallypriceless
observations.Aswellascorroboratingtheideathatintakeofdietaryglutenwaslinkedtothepresentationof
coeliacdisease,1scientificinvestigationsoffaminesurvivorsandtheiroffspringgaverisetotheideathat
preconceptualexposuretofaminemayhavetheabilitytoimprintonthegenesofoffspring.2Thusthelegacyof
theDutchfamine,whichledtothedeathofthousands,mayhavealsotouchedthelivesoffuturegenerations,
too.Thescienceofepigeneticswasborn.

Yourdestiny
TheideathatyourDNA,thefundamentalbuildingblocksoflife,maynotnecessarilybeyourdestinyisnota
newone.TheFrenchbiologistJeanBaptisteLamarck(17441829)coinedthenotionofsoftinheritanceasan
alternativetoDarwinism.
Lamarck,orratherLamarckism,becamesynonymouswiththeideathatanorganismcanpassontoitsoffspring
characteristicsthatitacquiredduringitslifetime.Inshort,environment,howeverthisistakentomean,mightbe
abletoleaveitsmarkonthegenome.
Thegenomerepresentsthesumtotalofapersonsbiologicaldataderivedfromtheirparents,encodedasDNA
(andRNA),theinstructionsforbuildingalltheproteinsrequiredtomakeuswhoweare.Alongthewaywe
pickupmutationsinthatgenomicinstructionmanualrepresentedassinglenucleotidepolymorphismsandother
changessuchascopynumbervariationsasaconsequenceofthingslikeourparentsageatconception3and
otherfactors.Indeed,theanalysisofsuchmutationsandtheirlinktohealthpredominatesmoderndaygenetics
research.

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DNAnotnecessarilyyourdestiny?Theroleofepigeneticsinpharmacy|News|PharmaceuticalJournal

Sciencenowrealises,however,thatoverandaboveourDNAinstructionmanual,thereresidesanotherlayer:
theepigenome.Thisconsistsofaseriesofchemicalcompoundsthathavetheabilitytomodifythefunctionof
thegenomeinprovidinginstructionseventuallyleadingtoswitchinggenesonandoff.Theepigenomeworks
inseveralways,primarilyincluding:
DNAmethylationAttachingmethylgroupstothebackboneofDNAmakesitpossibletoswitchgenesonor
off.Methylgroups,forexample,donatedbySadenosylmethionine,partofthemethioninehomocysteine
pathwayandintersectingonecarbonmetabolism,adheretocytosineinCpGdinucleotidesviavariousDNA
methyltransferases.MethylationofCpGislandsinthepromoterregionofageneinhibittheexpressionofthat
gene.
HistonemodificationIthasbeenestimatedthateachdiploidcellcontainsabouttwometresofDNA.4Thatisa
lotofDNAtofitintoacellnucleus.Inordertoaccomplishsuchafeat,chromosomalDNAiscompactedand
packagedupbyagroupofspecialproteinscalledhistonestoformachromatincomplex.Differentchargeskeep
therelationshipbetweenDNAandhistonestight.Histonescanbecovalentlymodified(posttranslational
modification)attheirtailsinavarietyofwaysthatsubsequentlyaltertheirholdonthepackagedDNAand,
indirectly,whatgenescanbeswitchedonoroff.Thevariouschemicalmodificationsrelevanttohistones
methylation,acetylation,phosphorylationmakeupthehistonecode,5agrowingcombinationofhistone
modifications.

Identicaltwinsarenotidentical
Despitesharingidenticalgenomes,evenidentical(monozygotic)twinscanbe
viewedasdifferentinepigenomicterms.6,7Varioustwinstudieshaveshown
discordancefordiseaseandriskofdiseasethoughttobeduetoepigenetic
differences,rangingfromchildhoodleukemia8toprimarybiliarycirrhosis.9
Althoughenvironmentalvariablesandexposurepatternsmayplayarolein
differentialdiseasepatternsintwins,thereisanincreasingfeelingthatepigenomic
differences,evenbeginninginutero,mayalsoshowinvolvement.
Ifwerecognisethemalleabilityoftheepigenome,ourquestionsthenturntowhatfactorscouldpotentially
causesuchepigeneticchangesandtheevidencefortheirpotentialrelationshiptohealthanddisease.Withinthis
context,lifestylechoicesandenvironmentalexposuresrepresentmodifiablevariablespotentiallyaffectingthe
expressionofDNA.

Diet,pollutantsandlifestyle
Dietisakeyfactorinepigenomics.Godfreyandcolleagues10suggestedarelationshipbetweenamaternallow
carbohydratedietandsubsequentgenemethylationrelatedtosubsequentoffspringweightgain.Perhapseven
moresurprisingisthesuggestionthatpaternaldietmayalsohavetheabilitytoinfluenceoffspringepigenomic
reprogramming,11atleastinthemousemodel.
Otherenvironmentalfactorsalsomayhaveabearingontheepigenome.Tobaccosmokingrepresentsonefactor
knowntoinfluenceDNAmethylationpatterns.Breitlingandcolleagues12reportedonalteredmethylation
patternsforageneofpotentialcardiovasculardrugtargetinterestinsmokerscomparedwithformersmokers
andnonsmokers.Flomandcolleagues13detailedasimilarlinkbetweenprenataltobaccosmokeexposureand
DNAmethylationissuesinadulthood.Otherenvironmentalpollutantshavesimilarlybeenreportedtomodify
epigeneticmarkers,14includingairborneparticulates,metalsandvariouspersistentorganicpollutants.
Perhapsevenmoresurprisingisthesuggestionthatsocietalinfluencesmayalsoimpactontheepigenome.
McGuinnessandcolleagues15reportedanassociationbetweensocioeconomicstatusandDNAmethylation,
citinghypomethylationasbeinglinkedtojobtypealongsidevariousmarkersofinflammation.Assumingsuch
anassociationisreplicated,thereareprofoundimplicationsforGovernmentpolicyandsociety,especiallyin
thecurrentclimateofausterity.

Epigeneticmedicines

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Withtheeverincreasingresearchfocusontheepigenome,thoughtsarealsoturningtothepossibilityof
pharmaceuticalepigeneticmodificationasatherapeuticoptionforvariousconditions.Certaintypesofcancer
havelongbeensuspectedtoincludeanepigeneticelement16followingthefindingsofhypermethylationof
promoterregionsoftumoursuppressinggenes,ineffectsilencingsuchgenes.
Variousareasofdrugdevelopmentareprogressing,including:
HistonedeacetylaseinhibitorsAbalancebetweenacetylationanddeacetylationoflysineresiduesinhistone
tailsisrequiredfornormalcellfunction.Alteredfunctioningofhistonedeacetylases(HDACs)andhistone
acetyltransferaseshasbeenreportedinvariouscancers17andotherconditions.HDACinhibitors,therefore,
representapotentialtherapeuticstrategy.Indeed,oneofthemostfamousantiepilepticmedicines,valproicacid,
isapotentHDACinhibitor18andisfindinganewroleinthisbravenewepigenomicworld.OtherHDAC
inhibitorformulationsincludevorinostat(Zolinza,Merck&Co)usedforthecutaneousmanifestationsofTcell
lymphoma.
DNAmethyltransferaseinhibitorsDNAmethyltransferasesrepresentpotentialtherapeutictargetsin
conditionsofhypermethylation.19SeveralformulationscategorisedasDNAmethyltransferaseinhibitorshave
beentrialled,includingazacytidine(Vidaza,Celgene)anddecitabine(Dacogen,AstexPharmaceuticals),both
indicatedformyelodysplasticsyndromes.

Thefutureoftheepigenome
Thereislittledoubtthatthestudyoftheepigenomeisfastbecominganintegralpartofthewayscienceviews
healthanddisease,intersectingbothgeneticandenvironmentalinfluences.Whereoncegeneswereseenas
immutableandafixedroadmaptoourpredispositiontohealthorillhealth,theabilitytomodifythefunctionof
thegenomeaddsadistinctivelayertoproceedings.Byunderstandingsuchmodifications,awidearrayof
possibilitiesareopenfordrugdevelopmentandmanagingdiseasesandtheirrisk.Indeed,thenotionthatthe
environmentmayhaveasignificanteffectontheepigenomecarriesimportantconsiderationsonthevarious
policiesforthepromotionofahealthylifestyle.
KalliopiDodouisseniorlecturerinpharmaceutics,SunderlandPharmacySchool,UniversityofSunderland.
PaulWhiteleyisaresearcherbasedintheNorthEastofEngland.Correspondenceto:KalliopiDodou(email
kalliopi.dodou@sunderland.ac.uk)

References

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glutenfreediet.Gut199334:14735.
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inpsychiatry.AmericanJournalofMedicalGenetics2009151C:13641.
7CzyzW.Genetic,environmentalandstochasticfactorsinmonozygotictwindiscordancewithafocuson
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8GaletzkaD.MonozygotictwinsdiscordantforconstitutiveBRCA1promotermethylation,childhoodcancer
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Citation:ThePharmaceuticalJournal,Vol.290,p23|URI:11114396

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