1Mechanismsofinterplaybetweentranscriptionfactorsandthe3DgenomeSeungsooKim1,JayShendure1,2,3*1DepartmentofGenomeSciences,UniversityofWashington,Seattle,WA981952HowardHughesMedicalInstitute,Seattle,WA981953BrotmanBatyInstituteforPrecisionMedicine,Seattle,WA98195*LeadContactAbstractTranscriptionfactors(TFs)bindDNAinasequence-specificmannerandtherebyserveastheproteinanchorsanddeterminantsof3Dgenomeorganization.Conversely,chromatinconformationshapesTFactivity,forexamplebyloopingTF-boundenhancerstodistallylocatedtargetgenes.Despiteconsiderableeffort,ourunderstandingofthemechanisticrelationshipbetweenTFsand3Dgenomeorganizationremainslimited,inlargepartduetothisinterdependency.Inthisreview,wesummarizetheevidenceforthediversemechanismsbywhichTFsandtheiractivityshapethe3Dgenome,andviceversa.WefurtherhighlightoutstandingquestionsandpotentialapproachesforuntanglingthecomplexrelationshipbetweenTFactivityandthe3Dgenome.2IntroductionTranscriptionfactors(TFs)areproteinsthatplayakeyroleinregulatinggeneexpressionbyrecognizinganddirectlybindingspecificDNAsequences(Lambertetal.,2018).UponbindingDNA,TFscanactivatetranscriptionbydirectly(Chernukhinetal.,2007)orindirectly(viacofactors)bringingRNAPolymeraseIIandothertranscriptionalmachinerytothepromotersequenceatthestartofagene(AllenandTaatjes,2015).Alternatively,theycanrepresstranscriptionbyrecruitingcorepressorsorinterferingwiththebindingofotherTFs(BraunandJohnson,1997;Moodyetal.,2005).SomeTFbindingsitesoccurnearpromoters,butinmammaliangenomes,theoverwhelmingmajorityoccurinclustersofbindingsitestermedenhancers,whicharetypicallytenstohundredsofkilobasesawayfromthepromoterstheyactivate(Gasperinietal.,2019).Theactionatadistanceofenhancersisthoughttobemediatedbythethree-dimensionalloopingofDNAthatbringsanenhancerintophysicalproximitywithapromoter(FurlongandLevine,2018).Towardsassessingwhetherthisisauniversalphenomenon,recenttechnicaladvanceshaveenabledincreasinglycomprehensiveandhigh-resolutionviewsofchromosomeconformation(Bonevetal.,201...
