Cellfatesandcomplexbodyplansareestablishedthroughanelaboratesuccessionofsignalsthatdefinecomplexandprecisepatternsofgeneexpression.Geneticstudieshaveuncoveredhighlyregulatedpro-gramsofgeneexpression,whicharegovernedbylargeinterconnectedregulatorynetworks(recentlyreviewedinREFS1,2)thatdrivethestereotypicdevelopmentofembryos.However,thistightlyregulatedviewofdevel-opmentalnetworksisatoddswithrecentglobaldatarevealingmanyfeatures—includingstochasticgeneexpression,bidirectionalpromoters,pervasivetran-scriptionandwidespreadbindingoftranscriptionfac-tors(TFs)—thatsuggesttranscriptionalregulationmaybearather‘leaky’process.ThisreviewfocusesontheoperationalpropertiesofTFsatenhancerele-mentsandaimstobridgethecurrentviewsoftran-scriptionthatareemergingfromgenomicstudiesandourunderstandingofthehighlyorderedprocessofdevelopmentasshownbygeneticstudies.Geneexpressionisregulatedthroughtheintegratedactionofmanycis-regulatoryelements,includingcorepromotersandpromoter-proximalelements(recentlyreviewedinREF.3),aswellasavariouscis-regulatorymodulesthatarelocalizedatgreaterdistancesfromthetranscriptionstartsites(TSSs),suchasenhancers4,5,silencers6–8,insulators9andtetheringelements10,11.Amongthisconstellationofelements,enhancersandtheirassociatedTFshavealeadingroleintheinitiationofgeneexpression,andidentifyingenhancerlocationshasbeenamajorfocusofmanystudies.EnhancersaresmallsegmentsofDNA,typicallyafewhundredbasepairs(bp)inlength,thatserveasoperationalplatformstorecruitTFsthroughshort,specificDNAsequences(motifs)toregulatetranscription.Theyhavetheinher-entcapacitytofunctioninamodularandautonomousmanner,withsomeexceptions(BOX1).HowthesepiecesofDNAgiverisetocomplexpatternsoftem-poralandspatialactivity,andhowTFsinterpretthegenometo‘read’therightsequencesattherighttimeofdevelopment,havebeenthesubjectofintensiveinvestigationsincethediscoveryofenhancerssome30yearsago12.Informationonthegenome-wideoccu-pancyofindividualTFshasprovidednovelandimpor-tantinsightsintotheiractivities.However,a...
