Regulation of gene expression - Wikipedia

Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of ... Regulationofgeneexpression FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Modifyingmechanismsusedbycellstoincreaseordecreasetheproductionofspecific geneproducts "Genemodulation"redirectshere.Forinformationontherapeuticregulationofgeneexpression,seetherapeuticusesgenemodulation. Forvocabulary,seeGlossaryofgeneexpressionterms. Regulationofgeneexpressionbyahormonereceptor DiagramshowingatwhichstagesintheDNA-mRNA-proteinpathwayexpressioncanbecontrolled Regulationofgeneexpression,orgeneregulation,[1]includesawiderangeofmechanismsthatareusedbycellstoincreaseordecreasetheproductionofspecificgeneproducts(proteinorRNA).Sophisticatedprogramsofgeneexpressionarewidelyobservedinbiology,forexampletotriggerdevelopmentalpathways,respondtoenvironmentalstimuli,oradapttonewfoodsources.Virtuallyanystepofgeneexpressioncanbemodulated,fromtranscriptionalinitiation,toRNAprocessing,andtothepost-translationalmodificationofaprotein.Often,onegeneregulatorcontrolsanother,andsoon,inageneregulatorynetwork. Generegulationisessentialforviruses,prokaryotesandeukaryotesasitincreasestheversatilityandadaptabilityofanorganismbyallowingthecelltoexpressproteinwhenneeded.Althoughasearlyas1951,BarbaraMcClintockshowedinteractionbetweentwogeneticloci,Activator(Ac)andDissociator(Ds),inthecolorformationofmaizeseeds,thefirstdiscoveryofageneregulationsystemiswidelyconsideredtobetheidentificationin1961ofthelacoperon,discoveredbyFrançoisJacobandJacquesMonod,inwhichsomeenzymesinvolvedinlactosemetabolismareexpressedbyE.colionlyinthepresenceoflactoseandabsenceofglucose. Inmulticellularorganisms,generegulationdrivescellulardifferentiationandmorphogenesisintheembryo,leadingtothecreationofdifferentcelltypesthatpossessdifferentgeneexpressionprofilesfromthesamegenomesequence.Althoughthisdoesnotexplainhowgeneregulationoriginated,evolutionarybiologistsincludeitasapartialexplanationofhowevolutionworksatamolecularlevel,anditiscentraltothescienceofevolutionarydevelopmentalbiology("evo-devo"). Contents 1Regulatedstagesofgeneexpression 2ModificationofDNA 2.1Structural 2.2Chemical 3Regulationoftranscription 4RegulationbyRNA 5Epigeneticgeneregulation 6Specialcasesinhumanbiologyanddisease 6.1Regulationoftranscriptionincancer 6.2Regulationoftranscriptioninaddiction 6.3Regulationoftranscriptioninlearningandmemory 7Post-transcriptionalregulation 8ThreeprimeuntranslatedregionsandmicroRNAs 9Regulationoftranslation 10Examplesofgeneregulation 10.1Developmentalbiology 11Circuitry 11.1Up-regulationanddown-regulation 11.2Induciblevs.repressiblesystems 11.3Theoreticalcircuits 12Studymethods 13Seealso 14Notesandreferences 15Bibliography 16Externallinks Regulatedstagesofgeneexpression[edit] Anystepofgeneexpressionmaybemodulated,fromsignalingtotranscriptiontopost-translationalmodificationofaprotein.Thefollowingisalistofstageswheregeneexpressionisregulated,themostextensivelyutilizedpointisTranscriptionInitiation: Signaltransduction Chromatin,chromatinremodeling,chromatindomains Transcription Post-transcriptionalmodification RNAtransport Translation mRNAdegradation ModificationofDNA[edit] Histonetailsandtheirfunctioninchromatinformation Ineukaryotes,theaccessibilityoflargeregionsofDNAcandependonitschromatinstructure,whichcanbealteredasaresultofhistonemodificationsdirectedbyDNAmethylation,ncRNA,orDNA-bindingprotein.Hencethesemodificationsmayupordownregulatetheexpressionofagene.Someofthesemodificationsthatregulategeneexpressionareinheritableandarereferredtoasepigeneticregulation. Structural[edit] TranscriptionofDNAisdictatedbyitsstructure.Ingeneral,thedensityofitspackingisindicativeofthefrequencyoftranscription.OctamericproteincomplexescalledhistonestogetherwithasegmentofDNAwoundaroundtheeighthistoneproteins(togetherreferredtoasanucleosome)areresponsiblefortheamountofsupercoilingofDNA,andthesecomplexescanbetemporarilymodifiedbyprocessessuchasphosphorylationormorepermanentlymodifiedbyprocessessuchasmethylation.Suchmodificationsareconsideredtoberesponsibleformoreorlesspermanentchangesingeneexpressionlevels.[2] Chemical[edit] MethylationofDNAisacommonmethodofgenesilencing.DNAistypicallymethylatedbymethyltransferaseenzymesoncytosinenucleotidesinaCpGdinucleotidesequence(alsocalled"CpGislands"whendenselyclustered).AnalysisofthepatternofmethylationinagivenregionofDNA(whichcanbeapromoter)canbeachievedthroughamethodcalledbisulfitemapping.Methylatedcytosineresiduesareunchangedbythetreatment,whereasunmethylatedonesarechangedtouracil.ThedifferencesareanalyzedbyDNAsequencingorbymethodsdevelopedtoquantifySNPs,suchasPyrosequencing(Biotage)orMassArray(Sequenom),measuringtherelativeamountsofC/TattheCGdinucleotide.Abnormalmethylationpatternsarethoughttobeinvolvedinoncogenesis.[3] Histoneacetylationisalsoanimportantprocessintranscription.Histoneacetyltransferaseenzymes(HATs)suchasCREB-bindingproteinalsodissociatetheDNAfromthehistonecomplex,allowingtranscriptiontoproceed.Often,DNAmethylationandhistonedeacetylationworktogetheringenesilencing.ThecombinationofthetwoseemstobeasignalforDNAtobepackedmoredensely,loweringgeneexpression.[citationneeded] Regulationoftranscription[edit] Mainarticle:Transcriptionalregulation 1:RNAPolymerase,2:Repressor,3:Promoter,4:Operator,5:Lactose,6:lacZ,7:lacY,8:lacA.Top:Thegeneisessentiallyturnedoff.Thereisnolactosetoinhibittherepressor,sotherepressorbindstotheoperator,whichobstructstheRNApolymerasefrombindingtothepromoterandmakinglactase.Bottom:Thegeneisturnedon.Lactoseisinhibitingtherepressor,allowingtheRNApolymerasetobindwiththepromoter,andexpressthegenes,whichsynthesizelactase.Eventually,thelactasewilldigestallofthelactose,untilthereisnonetobindtotherepressor.Therepressorwillthenbindtotheoperator,stoppingthemanufactureoflactase. RegulationoftranscriptionthuscontrolswhentranscriptionoccursandhowmuchRNAiscreated.TranscriptionofagenebyRNApolymerasecanberegulatedbyseveralmechanisms. SpecificityfactorsalterthespecificityofRNApolymeraseforagivenpromoterorsetofpromoters,makingitmoreorlesslikelytobindtothem(i.e.,sigmafactorsusedinprokaryotictranscription). RepressorsbindtotheOperator,codingsequencesontheDNAstrandthatareclosetooroverlappingthepromoterregion,impedingRNApolymerase'sprogressalongthestrand,thusimpedingtheexpressionofthegene.Theimagetotherightdemonstratesregulationbyarepressorinthelacoperon. GeneraltranscriptionfactorspositionRNApolymeraseatthestartofaprotein-codingsequenceandthenreleasethepolymerasetotranscribethemRNA. ActivatorsenhancetheinteractionbetweenRNApolymeraseandaparticularpromoter,encouragingtheexpressionofthegene.ActivatorsdothisbyincreasingtheattractionofRNApolymeraseforthepromoter,throughinteractionswithsubunitsoftheRNApolymeraseorindirectlybychangingthestructureoftheDNA. EnhancersaresitesontheDNAhelixthatareboundbyactivatorsinordertolooptheDNAbringingaspecificpromotertotheinitiationcomplex.Enhancersaremuchmorecommonineukaryotesthanprokaryotes,whereonlyafewexamplesexist(todate).[4] SilencersareregionsofDNAsequencesthat,whenboundbyparticulartranscriptionfactors,cansilenceexpressionofthegene. RegulationbyRNA[edit] RNAcanbeanimportantregulatorofgeneactivity,e.g.bymicroRNA(miRNA),antisense-RNA,orlongnon-codingRNA(lncRNA).LncRNAsdifferfrommRNAsinthesensethattheyhavespecifiedsubcellularlocationsandfunctions.Theywerefirstdiscoveredtobelocatedinthenucleusandchromatin,andthelocalizationsandfunctionsarehighlydiversenow.Somestillresideinchromatinwheretheyinteractwithproteins.WhilethislncRNAultimatelyaffectsgeneexpressioninneuronaldisorderssuchasParkinson,Huntington,andAlzheimerdisease,others,suchas,PNCTR(pyrimidine-richnon-codingtranscriptors),playaroleinlungcancer.Giventheirroleindisease,lncRNAsarepotentialbiomarkersandmaybeusefultargetsfordrugsorgenetherapy,althoughtherearenoapproveddrugsthattargertlncRNAsyet.TherenumberoflncRNAsinthehumangenomeremainspoorlydefined,butsomeestimatesrangefrom16,000to100,000lncgenes.[5] Epigeneticgeneregulation[edit] OverviewofEpigeneticmechanisms. EpigeneticsreferstothemodificationofgenesthatisnotchangingtheDNAorRNAsequence.Epigeneticmodificationsarealsoakeyfactorininfluencinggeneexpression.TheyoccurongenomicDNAandhistonesandtheirchemicalmodificationsregulategeneexpressioninamoreefficientmanner.ThereareseveralmodificationsofDNA(usuallymethylation)andmorethan100modificationsofRNAinmammaliancells.”ThosemodificationsresultinalteredproteinbindingtoDNAandachangeinRNAstabilityandtranslationefficiency.[6] Specialcasesinhumanbiologyanddisease[edit] Regulationoftranscriptionincancer[edit] Mainarticle:Regulationoftranscriptionincancer Invertebrates,themajorityofgenepromoterscontainaCpGislandwithnumerousCpGsites.[7]Whenmanyofagene'spromoterCpGsitesaremethylatedthegenebecomessilenced.[8]Colorectalcancerstypicallyhave3to6drivermutationsand33to66hitchhikerorpassengermutations.[9]However,transcriptionalsilencingmaybeofmoreimportancethanmutationincausingprogressiontocancer.Forexample,incolorectalcancersabout600to800genesaretranscriptionallysilencedbyCpGislandmethylation(seeregulationoftranscriptionincancer).Transcriptionalrepressionincancercanalsooccurbyotherepigeneticmechanisms,suchasalteredexpressionofmicroRNAs.[10]Inbreastcancer,transcriptionalrepressionofBRCA1mayoccurmorefrequentlybyover-expressedmicroRNA-182thanbyhypermethylationoftheBRCA1promoter(seeLowexpressionofBRCA1inbreastandovariancancers). Regulationoftranscriptioninaddiction[edit] Oneofthecardinalfeaturesofaddictionisitspersistence.Thepersistentbehavioralchangesappeartobeduetolong-lastingchanges,resultingfromepigeneticalterationsaffectinggeneexpression,withinparticularregionsofthebrain.[11]Drugsofabusecausethreetypesofepigeneticalterationinthebrain.Theseare(1)histoneacetylationsandhistonemethylations,(2)DNAmethylationatCpGsites,and(3)epigeneticdownregulationorupregulationofmicroRNAs.[11][12](SeeEpigeneticsofcocaineaddictionforsomedetails.) Chronicnicotineintakeinmicealtersbraincellepigeneticcontrolofgeneexpressionthroughacetylationofhistones.ThisincreasesexpressioninthebrainoftheproteinFosB,importantinaddiction.[13]Cigaretteaddictionwasalsostudiedinabout16,000humans,includingneversmokers,currentsmokers,andthosewhohadquitsmokingforupto30years.[14]Inbloodcells,morethan18,000CpGsites(oftheroughly450,000analyzedCpGsitesinthegenome)hadfrequentlyalteredmethylationamongcurrentsmokers.TheseCpGsitesoccurredinover7,000genes,orroughlyathirdofknownhumangenes.ThemajorityofthedifferentiallymethylatedCpGsitesreturnedtothelevelofnever-smokerswithinfiveyearsofsmokingcessation.However,2,568CpGsamong942genesremaineddifferentiallymethylatedinformerversusneversmokers.Suchremainingepigeneticchangescanbeviewedas“molecularscars”[12]thatmayaffectgeneexpression. Inrodentmodels,drugsofabuse,includingcocaine,[15]methamphetamine,[16][17]alcohol[18]andtobaccosmokeproducts,[19]allcauseDNAdamageinthebrain.DuringrepairofDNAdamagessomeindividualrepaireventscanalterthemethylationofDNAand/ortheacetylationsormethylationsofhistonesatthesitesofdamage,andthuscancontributetoleavinganepigeneticscaronchromatin.[20] Suchepigeneticscarslikelycontributetothepersistentepigeneticchangesfoundinaddiction. Regulationoftranscriptioninlearningandmemory[edit] DNAmethylationistheadditionofamethylgrouptotheDNAthathappensatcytosine.Theimageshowsacytosinesingleringbaseandamethylgroupaddedontothe5carbon.Inmammals,DNAmethylationoccursalmostexclusivelyatacytosinethatisfollowedbyaguanine. Inmammals,methylationofcytosine(seeFigure)inDNAisamajorregulatorymediator.Methylatedcytosinesprimarilyoccurindinucleotidesequenceswherecytosineisfollowedbyaguanine,aCpGsite.ThetotalnumberofCpGsitesinthehumangenomeisapproximately28million.[21]andgenerallyabout70%ofallCpGsiteshaveamethylatedcytosine.[22] Theidentifiedareasofthehumanbrainareinvolvedinmemoryformation. Inarat,apainfullearningexperience,contextualfearconditioning,canresultinalife-longfearfulmemoryafterasingletrainingevent.[23]Cytosinemethylationisalteredinthepromoterregionsofabout9.17%ofallgenesinthehippocampusneuronDNAofaratthathasbeensubjectedtoabrieffearconditioningexperience.[24]Thehippocampusiswherenewmemoriesareinitiallystored. MethylationofCpGsinapromoterregionofagenerepressestranscription[25]whilemethylationofCpGsinthebodyofageneincreasesexpression.[26]TETenzymesplayacentralroleindemethylationofmethylatedcytosines.DemethylationofCpGsinagenepromoterbyTETenzymeactivityincreasestranscriptionofthegene.[27] Whencontextualfearconditioningisappliedtoarat,morethan5,000differentiallymethylatedregions(DMRs)(of500nucleotideseach)occurintherathippocampusneuralgenomebothonehourand24hoursaftertheconditioninginthehippocampus.[24]Thiscausesabout500genestobeup-regulated(oftenduetodemethylationofCpGsitesinapromoterregion)andabout1,000genestobedown-regulated(oftenduetonewlyformed5-methylcytosineatCpGsitesinapromoterregion).Thepatternofinducedandrepressedgeneswithinneuronsappearstoprovideamolecularbasisforformingthefirsttransientmemoryofthistrainingeventinthehippocampusoftheratbrain.[24] Post-transcriptionalregulation[edit] Mainarticle:Post-transcriptionalregulation AftertheDNAistranscribedandmRNAisformed,theremustbesomesortofregulationonhowmuchthemRNAistranslatedintoproteins.Cellsdothisbymodulatingthecapping,splicing,additionofaPoly(A)Tail,thesequence-specificnuclearexportrates,and,inseveralcontexts,sequestrationoftheRNAtranscript.Theseprocessesoccurineukaryotesbutnotinprokaryotes.Thismodulationisaresultofaproteinortranscriptthat,inturn,isregulatedandmayhaveanaffinityforcertainsequences. ThreeprimeuntranslatedregionsandmicroRNAs[edit] Mainarticle:Threeprimeuntranslatedregion Mainarticle:MicroRNA Threeprimeuntranslatedregions(3'-UTRs)ofmessengerRNAs(mRNAs)oftencontainregulatorysequencesthatpost-transcriptionallyinfluencegeneexpression.[28]Such3'-UTRsoftencontainbothbindingsitesformicroRNAs(miRNAs)aswellasforregulatoryproteins.Bybindingtospecificsiteswithinthe3'-UTR,miRNAscandecreasegeneexpressionofvariousmRNAsbyeitherinhibitingtranslationordirectlycausingdegradationofthetranscript.The3'-UTRalsomayhavesilencerregionsthatbindrepressorproteinsthatinhibittheexpressionofamRNA. The3'-UTRoftencontainsmiRNAresponseelements(MREs).MREsaresequencestowhichmiRNAsbind.Theseareprevalentmotifswithin3'-UTRs.Amongallregulatorymotifswithinthe3'-UTRs(e.g.includingsilencerregions),MREsmakeupabouthalfofthemotifs. Asof2014,themiRBasewebsite,[29]anarchiveofmiRNAsequencesandannotations,listed28,645entriesin233biologicspecies.Ofthese,1,881miRNAswereinannotatedhumanmiRNAloci.miRNAswerepredictedtohaveanaverageofaboutfourhundredtargetmRNAs(affectingexpressionofseveralhundredgenes).[30]Freidmanetal.[30]estimatethat>45,000miRNAtargetsiteswithinhumanmRNA3'-UTRsareconservedabovebackgroundlevels,and>60%ofhumanprotein-codinggeneshavebeenunderselectivepressuretomaintainpairingtomiRNAs. DirectexperimentsshowthatasinglemiRNAcanreducethestabilityofhundredsofuniquemRNAs.[31]OtherexperimentsshowthatasinglemiRNAmayrepresstheproductionofhundredsofproteins,butthatthisrepressionoftenisrelativelymild(lessthan2-fold).[32][33] TheeffectsofmiRNAdysregulationofgeneexpressionseemtobeimportantincancer.[34]Forinstance,ingastrointestinalcancers,a2015paperidentifiedninemiRNAsasepigeneticallyalteredandeffectiveindown-regulatingDNArepairenzymes.[35] TheeffectsofmiRNAdysregulationofgeneexpressionalsoseemtobeimportantinneuropsychiatricdisorders,suchasschizophrenia,bipolardisorder,majordepressivedisorder,Parkinson'sdisease,Alzheimer'sdiseaseandautismspectrumdisorders.[36][37][38] Regulationoftranslation[edit] Mainarticle:Translationalregulation ThetranslationofmRNAcanalsobecontrolledbyanumberofmechanisms,mostlyatthelevelofinitiation.RecruitmentofthesmallribosomalsubunitcanindeedbemodulatedbymRNAsecondarystructure,antisenseRNAbinding,orproteinbinding.Inbothprokaryotesandeukaryotes,alargenumberofRNAbindingproteinsexist,whichoftenaredirectedtotheirtargetsequencebythesecondarystructureofthetranscript,whichmaychangedependingoncertainconditions,suchastemperatureorpresenceofaligand(aptamer).Sometranscriptsactasribozymesandself-regulatetheirexpression. Examplesofgeneregulation[edit] Enzymeinductionisaprocessinwhichamolecule(e.g.,adrug)induces(i.e.,initiatesorenhances)theexpressionofanenzyme. TheinductionofheatshockproteinsinthefruitflyDrosophilamelanogaster. TheLacoperonisaninterestingexampleofhowgeneexpressioncanberegulated. Viruses,despitehavingonlyafewgenes,possessmechanismstoregulatetheirgeneexpression,typicallyintoanearlyandlatephase,usingcollinearsystemsregulatedbyanti-terminators(lambdaphage)orsplicingmodulators(HIV). Gal4isatranscriptionalactivatorthatcontrolstheexpressionofGAL1,GAL7,andGAL10(allofwhichcodeforthemetabolicofgalactoseinyeast).TheGAL4/UASsystemhasbeenusedinavarietyoforganismsacrossvariousphylatostudygeneexpression.[39] Developmentalbiology[edit] Mainarticle:Evolutionarydevelopmentalbiology Alargenumberofstudiedregulatorysystemscomefromdevelopmentalbiology.Examplesinclude: ThecolinearityoftheHoxgeneclusterwiththeirnestedantero-posteriorpatterning Patterngenerationofthehand(digits-interdigits):thegradientofsonichedgehog(secretedinducingfactor)fromthezoneofpolarizingactivityinthelimb,whichcreatesagradientofactiveGli3,whichactivatesGremlin,whichinhibitsBMPsalsosecretedinthelimb,resultsintheformationofanalternatingpatternofactivityasaresultofthisreaction–diffusionsystem. Somitogenesisisthecreationofsegments(somites)fromauniformtissue(Pre-somiticMesoderm).Theyareformedsequentiallyfromanteriortoposterior.Thisisachievedinamniotespossiblybymeansoftwoopposinggradients,Retinoicacidintheanterior(wavefront)andWntandFgfintheposterior,coupledtoanoscillatingpattern(segmentationclock)composedofFGF+NotchandWntinantiphase.[40] SexdeterminationinthesomaofaDrosophilarequiresthesensingoftheratioofautosomalgenestosexchromosome-encodedgenes,whichresultsintheproductionofsexlesssplicingfactorinfemales,resultinginthefemaleisoformofdoublesex.[41] Circuitry[edit] Mainarticle:Generegulatorynetwork Up-regulationanddown-regulation[edit] Up-regulationisaprocessthatoccurswithinacelltriggeredbyasignal(originatinginternalorexternaltothecell),whichresultsinincreasedexpressionofoneormoregenesandasaresulttheproteinsencodedbythosegenes.Conversely,down-regulationisaprocessresultingindecreasedgeneandcorrespondingproteinexpression. Up-regulationoccurs,forexample,whenacellisdeficientinsomekindofreceptor.Inthiscase,morereceptorproteinissynthesizedandtransportedtothemembraneofthecelland,thus,thesensitivityofthecellisbroughtbacktonormal,reestablishinghomeostasis. Down-regulationoccurs,forexample,whenacellisoverstimulatedbyaneurotransmitter,hormone,ordrugforaprolongedperiodoftime,andtheexpressionofthereceptorproteinisdecreasedinordertoprotectthecell(seealsotachyphylaxis). Induciblevs.repressiblesystems[edit] Generegulationworksusingoperatorsandrepressorsinbacteria. GeneRegulationcanbesummarizedbytheresponseoftherespectivesystem: Induciblesystems-Aninduciblesystemisoffunlessthereisthepresenceofsomemolecule(calledaninducer)thatallowsforgeneexpression.Themoleculeissaidto"induceexpression".Themannerbywhichthishappensisdependentonthecontrolmechanismsaswellasdifferencesbetweenprokaryoticandeukaryoticcells. Repressiblesystems-Arepressiblesystemisonexceptinthepresenceofsomemolecule(calledacorepressor)thatsuppressesgeneexpression.Themoleculeissaidto"repressexpression".Themannerbywhichthishappensisdependentonthecontrolmechanismsaswellasdifferencesbetweenprokaryoticandeukaryoticcells. TheGAL4/UASsystemisanexampleofbothaninducibleandrepressiblesystem.Gal4bindsanupstreamactivationsequence(UAS)toactivatethetranscriptionoftheGAL1/GAL7/GAL10cassette.Ontheotherhand,aMIG1responsetothepresenceofglucosecaninhibitGAL4andthereforestoptheexpressionoftheGAL1/GAL7/GAL10cassette.[42] Theoreticalcircuits[edit] Repressor/Inducer:anactivationofasensorresultsinthechangeofexpressionofagene negativefeedback:thegeneproductdownregulatesitsownproductiondirectlyorindirectly,whichcanresultin keepingtranscriptlevelsconstant/proportionaltoafactor inhibitionofrun-awayreactionswhencoupledwithapositivefeedbackloop creatinganoscillatorbytakingadvantageinthetimedelayoftranscriptionandtranslation,giventhatthemRNAandproteinhalf-lifeisshorter positivefeedback:thegeneproductupregulatesitsownproductiondirectlyorindirectly,whichcanresultin signalamplification bistableswitcheswhentwogenesinhibiteachotherandbothhavepositivefeedback patterngeneration Studymethods[edit] ForDNAandRNAmethods,seenucleicacidmethods. Forproteinmethods,seeproteinmethods. Ingeneral,mostexperimentsinvestigatingdifferentialexpressionusedwholecellextractsofRNA,calledsteady-statelevels,todeterminewhichgeneschangedandbyhowmuch.Theseare,however,notinformativeofwheretheregulationhasoccurredandmaymaskconflictingregulatoryprocesses(seepost-transcriptionalregulation),butitisstillthemostcommonlyanalysed(quantitativePCRandDNAmicroarray). Whenstudyinggeneexpression,thereareseveralmethodstolookatthevariousstages.Ineukaryotestheseinclude: ThelocalchromatinenvironmentoftheregioncanbedeterminedbyChIP-chipanalysisbypullingdownRNAPolymeraseII,Histone3modifications,Trithorax-groupprotein,Polycomb-groupprotein,oranyotherDNA-bindingelementtowhichagoodantibodyisavailable. Epistaticinteractionscanbeinvestigatedbysyntheticgeneticarrayanalysis Duetopost-transcriptionalregulation,transcriptionratesandtotalRNAlevelsdiffersignificantly.Tomeasurethetranscriptionratesnuclearrun-onassayscanbedoneandnewerhigh-throughputmethodsarebeingdeveloped,usingthiollabellinginsteadofradioactivity.[43] Only5%oftheRNApolymerisedinthenucleusexits,[44]andnotonlyintrons,abortiveproducts,andnon-sensetranscriptsaredegradated.Therefore,thedifferencesinnuclearandcytoplasmiclevelscanbeseebyseparatingthetwofractionsbygentlelysis.[45] Alternativesplicingcanbeanalysedwithasplicingarrayorwithatilingarray(seeDNAmicroarray). AllinvivoRNAiscomplexedasRNPs.ThequantityoftranscriptsboundtospecificproteincanbealsoanalysedbyRIP-Chip.Forexample,DCP2willgiveanindicationofsequesteredprotein;ribosome-boundgivesandindicationoftranscriptsactiveintranscription(althoughamoredatedmethod,calledpolysomefractionation,isstillpopularinsomelabs) ProteinlevelscanbeanalysedbyMassspectrometry,whichcanbecomparedonlytoquantitativePCRdata,asmicroarraydataisrelativeandnotabsolute. RNAandproteindegradationratesaremeasuredbymeansoftranscriptioninhibitors(actinomycinDorα-amanitin)ortranslationinhibitors(Cycloheximide),respectively. 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