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Chapter21RegulationofTranscription21.1Introduction
21.2Responseelementsidentifygenesundercommonregulation
21.3TherearemanytypesofDNA-bindingdomains
21.4AzincfingermotifisaDNA-bindingdomain
21.5Steroidreceptorsaretranscriptionfactors
21.6Steroidreceptorshavezincfingers
21.7Bindingtotheresponseelementisactivatedbyligand-binding
21.8Steroidreceptorsrecognizeresponseelementsbyacombinatorialcode
21.9HomeodomainsbindrelatedtargetsinDNA
21.10Helix-loop-helixproteinsinteractbycombinatorialassociation
21.11Leucinezippersareinvolvedindimerformation
21.12Transcriptioninitiationrequireschangesinchromatinstructure
21.13Chromatinremodelingisanactiveprocess
21.14Activationoftranscriptionrequireschangesinnucleosomeorganizationatthepromoter
21.15Histoneacetylationanddeacetylationcontrolchromatinactivity
21.16Polycombandtrithoraxareantagonisticrepressorsandactivators
21.17AnLCRmaycontroladomain
21.18Insulatorsblockenhanceractions
21.19Insulatorscanvaryinstrength
21.20Adomainhasseveraltypesofelements
21.21Geneexpressionisassociatedwithdemethylation
21.22CpGislandsareregulatorytargetsActivationofgenestructure
Initiationoftranscription
Processingthetranscript
Transporttocytoplasm
TranslationofmRNA21.1IntroductionTable21.1Incucibletranscriptionfactorsbindtoresponseelementsthatidentifygroupsofpromotersorenhancerssubjecttocoordinatecontrol.21.2ResponseelementsidentifygenesundercommonregulationRegulatoryAgentModuleConsensusFactorHeatshockHSECNNGAANNTCCNNGHSTFGlucocorticoidGRETGGTACAAATGTTCTReceptorPhorbolesterTRETGACTCAAP1SerumSRECCATATTAGGSRFFigure21.1Theregulatoryregionofahumanmetallothioneingenecontainsregulatorelementsinbothitspromoterandenhancer.Thepromoterhaselementsformetalinduction;anenhancerhasanelementforresponsetoglucocorticoid.Promoterelementsareshownabovethemap,andproteinsthatbindthemareindicatedbelow.
21.2ResponseelementsidentifygenesundercommonregulationFigure21.2Theactivityofaregulatorytranscriptionfactormaybecontrolledbysynthesisofprotein,covalentmodificationofprotein,ligandbinding,orbindingofinhibitorsthatsequestertheproteinoraffectitsabilitytobindtoDNA.21.3TherearemanytypesofDNA-bindingdomains
Figure28.19Oncogenesthatcodefortranscriptionfactorshavemutationsthatinactivatetranscription(v-erbAandpossiblyv-rel)orthatactivatetranscription(v-junandv-fos).21.3TherearemanytypesofDNA-bindingdomains
Figure21.3TranscriptionfactorSP1hasaseriesofthreezincfingers,eachwithacharacteristicpatternofcysteineandhistidineresiduesthatconstitutethezinc-bindingsite.21.4AzincfingermotifisaDNA-bindingdomainFigure21.4Zincfingersmayforma-helicesthatinsertintothemajorgroove,associatedwithb-sheetsontheotherside.21.4AzincfingermotifisaDNA-bindingdomainFigure21.5ThefirstfingerofasteroidreceptorcontrolsspecificityofDNA-binding(positionsshowninred);thesecondfingercontrolsspecificityofdimerization(positionsshowninblue).TheexpandedviewofthefirstfingershowsthatdiscriminationbetweenGREandEREtargetsequencesrestsontwoaminoacidsatthebase.21.4AzincfingermotifisaDNA-bindingdomainReceptorisatransmembraneprotein,locatedintheplasmamembrane,thatbindsaligandinadomainontheextracellularside,andasaresulthasachangeinactivityofthecytoplasmicdomain.(Thesametermissometimesusedalsoforthesteroidreceptors,whicharetranscriptionfactorsthatareactivatedbybindingligandsthataresteroidsorothersmallmolecules.)21.5Steroidreceptorshaveseveralindependentdomains
Figure21.6Severaltypesofhydrophobicsmallmoleculesactivatetranscriptionfactors.Corticoidsandsteroidsexhormonesaresynthesizedfromcholesterol,vitaminDisasteroid,thyroidhormonesaresynthesizedfromtyrosine,andretinoicacidissynthesizedfromisoprene(infishliver).21.5SteroidreceptorshaveseveralindependentdomainsFigure21.7Glucocorticoidsregulategenetranscriptionbycausingtheirreceptortobindtoanenhancerwhoseactionisneededforpromoterfunction.
21.5SteroidreceptorshaveseveralindependentdomainsFigure21.8Receptorsformanysteroidandthyroidhormoneshaveasimilarorganization,withanindividualN-terminalregion,conservedDNA-bindingregion,andaC-terminalhormone-bindingregion.21.5SteroidreceptorshaveseveralindependentdomainsFigure21.8Receptorsformanysteroidandthyroidhormoneshaveasimilarorganization,withanindividualN-terminalregion,conservedDNA-bindingregion,andaC-terminalhormone-bindingregion.21.5SteroidreceptorshaveseveralindependentdomainsFigure21.5ThefirstfingerofasteroidreceptorcontrolsspecificityofDNA-binding(positionsshowninred);thesecondfingercontrolsspecificityofdimerization(positionsshowninblue).TheexpandedviewofthefirstfingershowsthatdiscriminationbetweenGREandEREtargetsequencesrestsontwoaminoacidsatthebase.21.5SteroidreceptorshaveseveralindependentdomainsFigure21.19CoactivatorsmayhaveHATactivitiesthatacetylatethetailsofnucleosomalhistones.
21.5SteroidreceptorshaveseveralindependentdomainsFigure21.20Arepressorcomplexcontainsthreecomponents:aDNAbindingsubunit,acorepressor,andahistonedeacetylase.21.5SteroidreceptorshaveseveralindependentdomainsFigure21.9TRandRARbindtheSMRTcorepressorintheabsenceofligand.Thepromoterisnotexpressed.WhenSMRTisdisplacedbybindingofligand,thereceptorbindsacoactivatorcomplex.Thisleadstoactivationoftranscriptionbythebasalapparatus.21.5SteroidreceptorshaveseveralindependentdomainsFigure21.10ThehomeodomainmaybethesoleDNA-bindingmotifinatranscriptionalregulatorormaybecombinedwithothermotifs.Itrepresentsadiscrete(60residue)partoftheprotein.21.6HomeodomainsbindrelatedtargetsinDNAFigure21.11ThehomeodomainoftheAntennapediagenerepresentsthemajorgroupofgenescontaininghomeoboxesinDrosophila;engrailed(en)representsanothertypeofhomeoticgene;andthemammalianfactorOct-2representsadistantlyrelatedgroupoftranscriptionfactors.Thehomeodomainisconventionallynumberedfrom1to60.ItstartswiththeN-terminalarm,andthethreehelicalregionsoccupyresidues10-22,28-38,and42-58.21.6HomeodomainsbindrelatedtargetsinDNAFigure21.12Helix3ofthehomeodomainbindsinthemajorgrooveofDNA,withhelices1and2lyingoutsidethedoublehelix.Helix3contactsboththephosphatebackboneandspecificbases.TheN-terminalarmliesintheminorgroove,andmakesadditionalcontacts.
21.6HomeodomainsbindrelatedtargetsinDNAFigure29.8Theposteriorpathwayhastwobranches,responsibleforabdominaldevelopmentandgermcellformation.21.6HomeodomainsbindrelatedtargetsinDNAFigure21.13AllHLHproteinshaveregionscorrespondingtohelix1andhelix2,separatedbyaloopof10-24residues.BasicHLHproteinshavearegionwithconservedpositivechargesimmediatelyadjacenttohelix1.
21.7Helix-loop-helixproteinsinteractbycombinatorialassociation
Figure21.14AnHLHdimerinwhichbothsubunitsareofthebHLHtypecanbindDNA,butadimerinwhichonesubunitlacksthebasicregioncannotbindDNA.21.7Helix-loop-helixproteinsinteractbycombinatorialassociation
Figure21.15ThebasicregionsofthebZIPmotifareheldtogetherbythedimerizationattheadjacentzipperregionwhenthehydrophobicfacesoftwoleucinezippersinteractinparallelorientation.21.8LeucinezippersareinvolvedindimerformationFigure20.19Anenhancercontainsseveralstructuralmotifs.Thehistogramplotstheeffectofallmutationsthatreduceenhancerfunctionto<75%ofwildtype.Bindingsitesforproteinsareindicatedbelowthehistogram.21.8LeucinezippersareinvolvedindimerformationChromatinremodelingdescribestheenergy-dependentdisplacementorreorganizationofnucleosomesthatoccursinconjunctionwithactivationofgenesfortranscription.21.9Chromatinremodelingisanactiveprocess
Figure21.16Thepre-emptivemodelfortranscriptionofchromatinproposesthatifnucleosomesformatapromoter,transcriptionfactors(andRNApolymerase)cannotbind.Iftranscriptionfactors(andRNApolymerase)bindtothepromotertoestablishastablecomplexforinitiation,histonesareexcluded.21.9ChromatinremodelingisanactiveprocessFigure21.17ThedynamicmodelfortranscriptionofchromatinreliesuponfactorsthatcanuseenergyprovidedbyhydrolysisofATPtodisplacenucleosomesfromspecificDNAsequences.21.9ChromatinremodelingisanactiveprocessFigure21.18HormonereceptorandNF1cannotbindsimultaneouslytotheMMTVpromoterintheformoflinearDNA,butcanbindwhentheDNAispresentedonanucleosomalsurface.21.9ChromatinremodelingisanactiveprocessFigure21.18HormonereceptorandNF1cannotbindsimultaneouslytotheMMTVpromoterintheformoflinearDNA,butcanbindwhentheDNAispresentedonanucleosomalsurface.21.9ChromatinremodelingisanactiveprocessHAT(histoneacetyltransferase)enzymesmodifyhistonesbyadditionofacetylgroups;sometranscriptionalcoactivatorshaveHATactivity.
HDAC(histonedeacetyltransferase)enzymesremoveacetylgroupsfromhistones;theymaybeassociatedwithrepressorsoftranscription.21.10Histoneacetylationanddeacetylationcontrolchromatinactivity
Figure20.26Anupstreamtranscriptionfactormaybindacoactivatorthatcontactsthebasalapparatus.21.10HistoneacetylationanddeacetylationcontrolchromatinactivityFigure21.19CoactivatorsmayhaveHATactivitiesthatacetylatethetailsofnucleosomalhistones.21.10HistoneacetylationanddeacetylationcontrolchromatinactivityFigure21.20Arepressorcomplexcontainsthreecomponents:aDNAbindingsubunit,acorepressor,andahistonedeacetylase.21.10HistoneacetylationanddeacetylationcontrolchromatinactivityFigure21.21Pc-Gproteinsdonotinitiaterepression,butareresponsibleformaintainingit.21.11PolycombandtrithoraxareantagonisticrepressorsandactivatorsFigure19.45Extensionofheterochromatininactivatesgenes.Theprobabilitythatagenewillbeinactivateddependsonitsdistancefromtheheterochromatinregion.21.11PolycombandtrithoraxareantagonisticrepressorsandactivatorsDomainofachromosomemayrefereithertoadiscretestructuralentitydefinedasaregionwithinwhichsupercoilingisindependentofotherdomains;ortoanextensiveregionincludinganexpressedgenethathasheightenedsensitivitytodegradationbytheenzymeDNAaseI.
MAR(matrixattachmentsite;alsoknownasSARforscaffoldattachmentsite)isaregionofDNAthatattachestothenuclearmatrix.21.12Longrangeregulationandinsulationofdomains
Figure4.1Eachofthea-likeandb-likeglobingenefamiliesisorganizedintoasingleclusterthatincludesfunctionalgenesandpseudogenes(y).
21.12Longrangeregulationandinsulationofdomains
Figure4.1Eachofthea-likeandb-likeglobingenefamiliesisorganizedintoasingleclusterthatincludesfunctionalgenesandpseudogenes(y).
21.12Longrangeregulationandinsulationofdomains
Figure21.22Aglobindomainismarkedbyhypersensitivesitesateitherend.Thegroupofsitesatthe5¢sideconstitutestheLCRandisessentialforthefunctionofallgenesinthecluster.21.12Longrangeregulationandinsulationofdomains
Figure19.42SensitivitytoDNAaseIcanbemeasuredbydeterminingtherateofdisappearanceofthematerialhybridizingwithaparticularprobe.21.12Longrangeregulationandinsulationofdomains
Figure21.23SpecializedchromatinstructuresthatincludehypersensitivesitesmarktheendsofadomainintheD.melanogastergenomeandinsulategenesbetweenthemfromtheeffectsofsurroundingsequences.
21.12Longrangeregulationandinsulationofdomains
Figure21.24Aproteinthatbindstotheinsulatorscs¢islocalizedatinterbandsinDrosophilapolytenechromosomes.RedstainingidentifiestheDNA(thebands)onboththeupperandlowersamples;greenstainingidentifiesBEAF32(oftenatinterbands)ontheuppersample.Yellowshowscoincidenceofthetwolabels.Someofthemoreprominentstainedinterbandsaremarkedbywhitelines.PhotographkindlyprovidedbyUliLaemmli.21.12Longrangeregulationandinsulationofdomains
Figure21.25Theinsulatorofthegypsytransposonblockstheactionofanenhancerwhenitisplacedbetweentheenhancerandthepromoter.
21.12Longrangeregulationandinsulationofdomains
Figure29.32ThehomeoticgenesoftheANT-Ccomplexconferidentityonthemostanteriorsegmentsofthefly.Thegenesvaryinsize,andareinterspersedwithothergenes.Theantpgeneisverylargeandhasalternativeformsofexpression.21.12Longrangeregulationandinsulationofdomains
Figure21.26Fab-7isaboundaryelementthatisnecessaryfortheindependenceofregulatoryelementsiab-6andiab-7.21.12Longrangeregulationandinsulationofdomains
Figure21.27Domainsmaypossessthreetypesofsites:insulatorstopreventeffectsfromspreadingbetweendomains;MARstoattachthedomaintothenuclearmatrix;andLCRsthatarerequiredforinitiationoftranscription.21.12Longrangeregulationandinsulationofdomains
Figure21.28TherestrictionenzymeMspIcleavesallCCGGsequenceswhetherornottheyaremethylatedatthesecondC,butHpaIIcleavesonlynonmethylatedCCGGtetramers.21.13GeneexpressionisassociatedwithdemethylationFigure21.29TheresultsofMspIandHpaIIcleavagearecomparedbygelelectrophoresisofthefragments.
21.13GeneexpressionisassociatedwithdemethylationFigure13.30ReplicationofmethylatedDNAgiveshemimethylatedDNA,whichmaintainsitsstateatGATCsitesuntiltheDammethylaserestoresthefullymethylatedcondition.21.13GeneexpressionisassociatedwithdemethylationFigure21.30ThetypicaldensityofCpGdoubletsinmammalianDNAis~1/100bp,asseenforag-globingene.InaCpG-richisland,thedensityisincreasedto>10doublets/100bp.TheislandintheAPRTgenestarts~100bpupstreamofthepromoterandextends~400bpintothegene.EachverticallinerepresentsaCpGdoublet.21.13GeneexpressionisassociatedwithdemethylationFigure21.20Arepressorcomplexcontainsthreecomponents:aDNAbindingsubunit,acorepressor,andahistonedeacetylase.21.13
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