CombinatorialfunctionoftranscriptionfactorsandcofactorsFranziskaReiter*,SebastianWienerroither*andAlexanderStarkDifferentialgeneexpressiongivesrisetothemanycelltypesofcomplexorganisms.Enhancersregulatetranscriptionbybindingtranscriptionfactors(TFs),whichinturnrecruitcofactorstoactivateRNAPolymeraseIIatcorepromoters.TranscriptionalregulationistypicallymediatedbydistinctcombinationsofTFs,enablingarelativelysmallnumberofTFstogeneratealargediversityofcelltypes.However,howTFsachievecombinatorialenhancercontrolandhowenhancers,enhancer-boundTFs,andthecofactorstheyrecruitregulateRNAPolymeraseIIactivityisnotentirelyclear.Here,wereviewhowTFsynergyismediatedatthelevelofDNAbindingandafterbinding,theroleofcofactorsandthepost-translationalmodificationstheycatalyze,anddiscussdifferentmodelsofenhancer—core-promotercommunication.AddressResearchInstituteofMolecularPathology(IMP),ViennaBiocenter(VBC),Campus-Vienna-Biocenter1,1030Vienna,AustriaCorrespondingauthor:Stark,Alexander(stark@starklab.org)*Theseauthorscontributedequallytothiswork.CurrentOpinioninGenetics&Development2017,43:73–81ThisreviewcomesfromathemedissueonGenomearchitectureandexpressionEditedbyBartDeplanckeandCharlesSagerstromForacompleteoverviewseetheIssueandtheEditorialAvailableonline19thJanuary2017http://dx.doi.org/10.1016/j.gde.2016.12.0070959-437X/ã2017ElsevierLtd.Allrightsreserved.IntroductionGeneregulationiscentraltodevelopmentandcellulardifferentiation[1,2],anderroneousgeneexpressionislinkedtomanydiseasesincludingcancer[3,4].GeneregulatoryinformationisencodedintheDNAsequencesofgenomiccis-regulatoryelementscalledenhancers[5],whichactivateorrepresstranscriptionfromtheirtargetgenes’core-promoters[2].Differenttranscriptionfactors(TFs)bindtoshortrecognitionsiteswithinenhancers–thusessentiallyreadingtheregulatoryinformationcon-tainedintheenhancersequence–andrecruitcofactors(COFs),suchastheMediatorcomplexortheacetyl-transferaseCBP/p300.Together,theseregulatorypro-teinsmediateRNApolymeraseII(PolII)recruitmentanda...
