Publishedonline14November2019NucleicAcidsResearch,2019,Vol.47,No.2211497–11513doi:10.1093/nar/gkz1068SURVEYANDSUMMARYThechangingparadigmofintronretention:regulation,ramificationsandrecipesGeoffrayMonteuuis1,JustinJ.L.Wong2,3,CharlesG.Bailey1,2,UlfSchmitz1,2,4,*andJohnE.J.Rasko1,2,5,*1GeneandStemCellTherapyProgramCentenaryInstitute,TheUniversityofSydney,Camperdown,Australia,2FacultyofMedicineandHealth,TheUniversityofSydney,NSW2006,Australia,3EpigeneticsandRNABiologyProgramCentenaryInstitute,TheUniversityofSydney,Camperdown,Australia,4ComputationalBiomedicineLaboratoryCentenaryInstitute,TheUniversityofSydney,Camperdown,Australiaand5CellandMolecularTherapies,RoyalPrinceAlfredHospital,Camperdown,AustraliaReceivedMay08,2019;RevisedOctober04,2019;EditorialDecisionOctober28,2019;AcceptedOctober30,2019ABSTRACTIntronretention(IR)isaformofalternativesplic-ingthathaslongbeenneglectedinmammaliansys-temsalthoughithasbeenstudiedfordecadesinnon-mammalianspeciessuchasplants,fungi,in-sectsandviruses.Itwasgenerallyassumedthatmis-splicing,leadingtotheretentionofintrons,wouldhavenophysiologicalconsequenceotherthanre-ducinggeneexpressionbynonsense-mediatedde-cay.RelativelyrecentlandmarkdiscoverieshavehighlightedthepivotalrolethatIRservesinnormalanddisease-relatedhumanbiology.Significanttech-nicalhurdleshavebeenovercome,therebyenablingtherobustdetectionandquantificationofIR.Still,rel-ativelylittleisknownaboutthecis-andtrans-actingmodulatorscontrollingthisphenomenon.Thefateofanintrontobe,ornottobe,retainedinthema-turetranscriptisthedirectresultoftheinfluenceexertedbynumerousintrinsicandextrinsicfactorsatmultiplelevelsofregulation.Thesefactorshaveal-teredcurrentbiologicalparadigmsandprovidedun-expectedinsightsintothetranscriptionallandscape.Inthisreview,wediscusstheregulatorsofIRandmethodstoidentifythem.Ourfocusisprimarilyonmammals,however,webroadenthescopetonon-mammalianorganismsinwhichIRhasbeenshowntobebiologicallyrelevant.INTRODUCTIONTheoriginalassumptionthatonegeneencodesonlyonepol...
