Epigenome1.docx
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Epigenome1.docx
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Epigenome1
Epigenome
FromWikipedia,thefreeencyclopedia
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AnepigenomeconsistsofarecordofthechemicalchangestotheDNAandhistoneproteinsofanorganism;thesechangescanbepasseddowntoanorganism'soffspring.Changestotheepigenomecanresultinchangestothestructureofchromatinandchangestothefunctionofthegenome.[1]
Theepigenomeisinvolvedinregulatinggeneexpression,development,tissuedifferentiation,andsuppressionoftransposableelements.Unliketheunderlyinggenomewhichislargelystaticwithinanindividual,theepigenomecanbedynamicallyalteredbyenvironmentalconditions.
Cancer[edit]
Epigeneticsisacurrentlyactivetopicincancerresearch.HumantumorsundergoamajordisruptionofDNAmethylationandhistonemodificationpatterns.Theaberrantepigeneticlandscapeofthecancercellischaracterizedbyaglobalgenomichypomethylation,CpGislandpromoterhypermethylationoftumorsuppressorgenes,analteredhistonecodeforcriticalgenesandagloballossofmonoacetylatedandtrimethylatedhistoneH4.
Epigenomeresearchprojects[edit]
AsapreludetoapotentialHumanEpigenomeProject,theHumanEpigenomePilotProjectaimstoidentifyandcatalogueMethylationVariablePositions(MVPs)inthehumangenome.[2]Advancesinsequencingtechnologynowallowforassayinggenome-wideepigenomicstatesbymultiplemolecularmethodologies.[3]Micro-andnanoscaledeviceshavebeenconstructedorproposedtoinvestigatetheepigenome.[4]
AninternationalefforttoassayreferenceepigenomeshasrecentlycommencedintheformoftheInternationalHumanEpigenomeConsortium.
Roadmapepigenomicsproject[edit]
OnegoaloftheNIHRoadmapEpigenomicsProjectistogeneratehumanreferenceepigenomesfromnormal,healthyindividualsacrossalargevarietyofcelllines,primarycellsandprimarytissues.Dataproducedbytheproject,whichcanbebrowsedanddownloadedfromtheHumanEpigenomeAtlas,fallintofivetypesthatassaydifferentaspectsoftheepigenomeandoutcomesofepigenomicstates(suchasgeneexpression):
1.HistoneModifications-ChromatinImmunoprecipitationSequencing(ChIP-Seq)identifiesgenomewidepatternsofhistonemodificationsusingantibodiesagainstthemodifications.[5]
2.DNAMethylation-WholeGenomeBisulfite-Seq,ReducedRepresentationBisulfite-Seq(RRBS),MethylatedDNAImmunoprecipitationSequencing(MeDIP-Seq),andMethylation-sensitiveRestrictionEnzymeSequencing(MRE-Seq)identifyDNAmethylationacrossportionsofthegenomeatvaryinglevelsofresolutiondowntobasepairlevel.[6]
3.ChromatinAccessibility-DNaseIhypersensitivesitesSequencing(DNase-Seq)identifiesregionsofopenchromatin.
4.GeneExpression-RNA-Seqandexpressionarraysidentifyexpressionlevelsorproteincodinggenes.
5.SmallRNAExpression-smRNA-SeqidentifiesexpressionofsmallnoncodingRNA,primarilymiRNAs.
ReferenceepigenomesforhealthyindividualswillenablethesecondgoaloftheRoadmapEpigenomicsProject,whichistoexamineepigenomicdifferencesthatoccurindiseasestatessuchasAlzheimer'sdisease.
Bacterialtranscription
BacterialtranscriptionorprokaryotictranscriptionistheprocessinwhichmessengerRNAtranscriptsofgeneticmaterialinprokaryotesareproduced,tobetranslatedfortheproductionofproteins.Bacterialtranscriptionoccursinthecytoplasmalongsidetranslation.Unlikeineukaryotes,prokaryotictranscriptionandtranslationcanoccursimultaneously.Thisisimpossibleineukaryotes,wheretranscriptionoccursinamembrane-boundnucleuswhiletranslationoccursoutsidethenucleusinthecytoplasm.Inprokaryotesgeneticmaterialisnotenclosedinamembrane-enclosednucleusandhasaccesstoribosomesinthecytoplasm.[1]
Transcriptionisknowntobecontrolledbyavarietyofregulatorsinprokaryotes.Manyofthesetranscriptionfactorsarehomodimerscontaininghelix-turn-helixDNA-bindingmotifs.[2]
Initiation
Thefollowingstepsoccur,inorder,fortranscriptioninitiation:
∙RNApolymerase(RNAP)bindstooneofseveralspecificityfactors,蟽,toformaholoenzyme.Inthisform,itcanrecognizeandbindtospecificpromoterregionsintheDNA.The-35regionandthe-10("Pribnowbox")regioncomprisethecoreprokaryoticpromoter,and|T|standsfortheterminator.TheDNAonthetemplatestrandbetweenthe+1siteandtheterminatoristranscribedintoRNA,whichisthentranslatedintoprotein.Atthisstage,theDNAisdouble-stranded("closed").Thisholoenzyme/wound-DNAstructureisreferredtoastheclosedcomplex.
∙TheDNAisunwoundandbecomessingle-stranded("open")inthevicinityoftheinitiationsite(definedas+1).Thisholoenzyme/unwound-DNAstructureiscalledtheopencomplex.
∙TheRNApolymerasetranscribestheDNA(thebetasubunitinitiatesthesynthesis),butproducesabout10abortive(short,non-productive)transcriptswhichareunabletoleavetheRNApolymerasebecausetheexitchannelisblockedbythe蟽-factor.
∙The蟽-factoreventuallydissociatesfromthecoreenzyme,andelongationproceeds.
Elongation
Promoterscandifferin"strength";thatis,howactivelytheypromotetranscriptionoftheiradjacentDNAsequence.Promoterstrengthisinmany(butnotall)cases,amatterofhowtightlyRNApolymeraseanditsassociatedaccessoryproteinsbindtotheirrespectiveDNAsequences.Themoresimilarthesequencesaretoaconsensussequence,thestrongerthebindingis.Additionaltranscriptionregulationcomesfromtranscriptionfactorsthatcanaffectthestabilityoftheholoenzymestructureatinitiation.
Mosttranscriptsoriginateusingadenosine-5'-triphosphate(ATP)and,toalesserextent,guanosine-5'-triphosphate(GTP)(purinenucleosidetriphosphates)atthe+1site.Uridine-5'-triphosphate(UTP)andcytidine-5'-triphosphate(CTP)(pyrimidinenucleosidetriphosphates)aredisfavouredattheinitiationsite.
Termination
Twoterminationmechanismsarewellknown:
∙Intrinsictermination(alsocalledRho-independenttranscriptiontermination)involvesterminatorsequenceswithintheRNAthatsignaltheRNApolymerasetostop.Theterminatorsequenceisusuallyapalindromicsequencethatformsastem-loophairpinstructurethatleadstothedissociationoftheRNAPfromtheDNAtemplate.
∙Rho-dependentterminationusesaterminationfactorcalledρfactor(rhofactor)whichisaproteintostopRNAsynthesisatspecificsites.ThisproteinbindsatarhoutilisationsiteonthenascentRNAstrandandrunsalongthemRNAtowardstheRNAP.AstemloopstructureupstreamoftheterminatorregionpausestheRNAP,whenρ-factorreachestheRNAP,itcausesRNAPtodissociatefromtheDNA,terminatingtranscription.
Regulationofgeneexpression
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Genemodulationredirectshere.Forinformationontherapeuticregulationofgeneexpression,seetherapeuticgenemodulation.
Forvocabulary,seeGlossaryofgeneexpressionterms
DiagramshowingatwhichstagesintheDNA-mRNA-proteinpathwayexpressioncanbecontrolled
Regulationofgeneexpressionincludesawiderangeofmechanismsthatareusedbycellstoincreaseordecreasetheproductionofspecificgeneproducts(proteinorRNA),andisinformallytermedgeneregulation.Sophisticatedprogramsofgeneexpressionarewidelyobservedinbiology,forexampletotriggerdevelopmentalpathways,respondtoenvironmentalstimuli,oradapttonewfoodsources.Virtuallyanystepofgeneexpressioncanbemodulated,fromtranscriptionalinitiation,toRNAprocessing,andtothepost-translationalmodificationofaprotein.
Generegulationisessentialforviruses,prokaryotesandeukaryotesasitincreasestheversatilityandadaptabilityofanorganismbyallowingthecelltoexpressproteinwhenneeded.Althoughasearlyas1951BarbaraMcClintockshowedinteractionbetweentwogeneticloci,Activator(Ac)andDissociator(Ds),inthecolorformationofmaizeseeds,thefirstdiscoveryofageneregulationsystemiswidelyconsideredtobetheidentificationin1961ofthelacoperon,discoveredbyJacquesMonod,inwhichsomeenzymesinvolvedinlactosemetabolismareexpressedbythegenomeofE.colionlyinthepresenceoflactoseandabsenceofglucose.
Furthermore,inmulticellularorganisms,generegulationdrivestheprocessesofcellulardifferentiationandmorphogenesis,leadingtothecreationofdifferentcelltypesthatpossessdifferentgeneexpressionprofiles,andhenceproducedifferentproteins/havedifferentultrastructuresthatsuitthemtotheirfunctions(thoughtheyallpossessthegenotype,whichfollowsthesamegenomesequence).
Theinitiatingeventleadingtoachangeingeneexpressionincludeactivationordeactivationofreceptors.Also,thereisevidencethatchangesinacell'schoiceofcatabolismleadstoalteredgeneexpressions.[1]
Contents
[hide]
∙1Regulatedstagesofgeneexpression
∙2ModificationofDNA
o2.1Structural
o2.2Chemical
∙3Regulationoftranscription
∙4Post-transcriptionalregulation
∙5Regulationoftranslation
∙6Examplesofgeneregulation
o6.1Developmentalbiology
∙7Circuitry
o7.1Up-regulationanddown-regulation
o7.2Induciblevs.repressiblesystems
o7.3Theoreticalcircuits
∙8Studymethods
∙9Seealso
∙10Notesandreferences
∙11Bibliography
∙12Externallinks
Regulatedstagesofgeneexpression[edit]
Anystepofgeneexpressionmaybemodulated,fromtheDNA-RNAtranscriptionsteptopost-translationalmodificationofaprotein.Thefollowingisalistofstageswheregeneexpressionisregulated,themostextensivelyutilisedpointisTranscriptionInitiation:
∙Chromatindomains
∙Transcription
∙Post-trans
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