Long non-coding RNAs and control of gene expression in the immune system53
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Long non-coding RNAs and control of gene expression in the immune system53
Review；Longnon-codingRNAsandcon；ManinjayK.AtianandandKat；PrograminInnateImmunity,；Allcellsoftheimmunesyste；Theimmunesystemandnon-co；Theimmunesystemisequippe；RegulatoryRNAsarenon-pr
ReviewLongnon-codingRNAsandcontrolofgeneexpressionintheimmunesystemManinjayK.AtianandandKatherineA.FitzgeraldPrograminInnateImmunity,DivisionofInfectiousDiseasesandImmunology,DepartmentofMedicine,UniversityofMassachusettsMedicalSchool,Worcester,MA,USAAllcellsoftheimmunesystemrelyonahighlyintegrat-edanddynamicgeneexpressionprogramthatiscon-trolledbybothtranscriptionalandpost-transcriptionalmechanisms.Recently,non-codingRNAs,includinglongnon-codingRNAs(lncRNAs),haveemergedasimportantregulatorsofgeneexpressionindiversebiologicalcon-texts.lncRNAscontrolgeneexpressioninthenucleusbymodulatingtranscriptionorviapost-transcriptionalmechanismstargetingthesplicing,stability,ortransla-tionofmRNAs.OurknowledgeoflncRNAbiogenesis,theircelltype-speci?cexpression,andtheirversatilemolecularfunctionsisrapidlyprogressinginallareasofbiology.Wediscussheretheseexcitingnewregula-torsandhighlightanemergingparadigmoflncRNA-mediatedcontrolofgeneexpressionintheimmunesystem.Theimmunesystemandnon-codingRNAsTheimmunesystemisequippedwithanarsenalofstrate-giestocombatinfectiousthreatsandmaintainnormalhealth.Thisismediatedbyspecializedimmunecellsdedi-catedtocarryingoutsophisticatedandhighlyintegratedfunctionsoftheinnateandadaptivearmsoftheimmunesystem.Thedevelopmentandactivationstateofimmunecellsisdependentonatightlyregulatedandintegratedgene-expressionprogramcontrolledbywell-establishedtranscriptionfactorsandchromatin-modifyingcomplexes.Ourknowledgeofthefunctionalrolesofproteinsinthetranscriptionalandpost-transcriptionalregulationofgeneexpressionihowever,wehaveonlybeguntoappreciatethefundamentalrolesofregulatoryRNAsincontrollingallfacetsofgeneexpression.RegulatoryRNAsarenon-protein-codingtranscriptsthatmediatetheirfunctionsstrictlyasRNAmolecules[1].Someofthese,includingsmallnuclearRNA(snRNA),smallnucleolarRNA(snoRNA),ribosomalRNA(rRNA),andtransferRNA(tRNA),havebeenknownfordecades.Theyareimportantplayersinessentialbiologicalprocess-esincludingchromatin/nuclearorganization(snRNAandsnoRNA),mRNAsplicing(snRNA),ribosomebiogenesisandassembly(rRNA),andtranslation(tRNA)[2].ThediscoveryofRNAinterference(RNAi)mediatedbysiRNACorrespondingauthor:Fitzgerald,K.A.(kate.fitzgerald@umassmed.edu).Keywords:longnon-codingRNA;lncRNA;lincRNA;geneexpres-epigenetics./?2014ElsevierLtd.Allrightsreserved.http://dx.doi.org/10.1016/j.molmed.andmiRNAledtoanewparadigmingeneregulationbydemonstratingthatshortcomplementaryRNAscandirect-lyregulatetargetmRNAs[3C5].Morerecently,anewclassofregulatoryRNAsknownaslncRNAshasemergedasanadditionallayerofthecircuitrycontrollinggeneexpression[6,7].OurunderstandingofthefunctionalrolesoflncRNAsincontrollinggeneexpressionisevolving,andisrede?ningourbasicunderstandingofbiology.Intheimmunesystem,lncRNAsexhibitdynamicexpressionincelltype-,develop-mentalstage-,andcontext-speci?cmannerstocoordinateseveralaspectsofimmunefunction.WedescribehereourcurrentknowledgeoftheseRNAsintheimmunesystem.lncRNAs:darkmatterofthegenometakesthecenterstageOneofthemanyunexpectedsurprisesfromtheEncyclo-pediaofDNAElements(ENCODE)consortium,foundedin2003,wasthatthevastmajorityofthemammaliangenomeistranscribed[8,9].AccordingtothelatestGENCODEversion19(http://www.gencodegenes.org),itisestimatedthatonly??2%ofthemammaliangenomeiscomposedofgenesthatencodeproteins,whilethevastmajority(75C90%)istranscribedasnon-codingRNA[10,11].LncRNAs(13870inthehumanand4074inthemousegenome)accountformostofthispervasivetranscription(Figure1).High-throughputtranscriptomesequencinghasledtothediscoveryofthousandsoflncRNAgenes,andthesenum-bersarestillgrowing[12,13].Ingeneral,lncRNAsarede?nedasnonprotein-codingtranscriptslargerthan200nucleotides.InclusionofthesizecriterionisprimarilyemployedtodistinguishlncRNAsfromsmallerncRNAspeciessuchassiRNA,miRNA,andothers.ThemajorityoflncRNAssharefeaturesofprotein-codingmRNAsbecausetheyarecapped,polyadenylated,andspliced[14,15].AnimportantfeatureoflncRNAsistheirlackofprotein-however,aswithanynega-tive?nding,itisdif?culttoprovetheabsenceofencodedprotein/peptidewithabsolutecertainty.ThisaspectoflncRNAbiologyremainssomewhatcontroversial[16C18].Therefore,itiscrucialthatlncRNAfunctionalityisstrictlyattributedtotheRNA(andnottoapotentiallyencodedprotein).Computationalapproaches(predictionofopenreadingframes,codon-substitutionfrequency,andevolutionaryconservation)aswellasexperimentalapproaches(invitrotranscriptionandtranslation,polysomeassociation,andribosomefootprintingfollowedbyRNA-seq)areroutinelyemployedtoaddresstheprotein-codingpotentialoflncRNAs[14,15].ItispossiblethatsomeTrendsinMolecularMedicine,November2014,Vol.20,No.11623ReviewTrendsinMolecularMedicineNovember2014,Vol.20,No.11Figure1.Longnon-codingRNAs(lncRNAs)arethemostabundantncRNAspeciesinthemammaliangenome.(A)Piechartsshowingthegenome-widedistributionofprotein-andnon-codinggenesinthehumanandmicegenomes.NumbersshownarecalculatedfromtheGENCODEversion19(July2013http://www.gencodegenes.org).(B)ClassificationoflncRNAsbasedontheirgenomiclocalizationwithrespecttotheneighboringprotein-codinggene.LncRNAsingeneralareclassifiedasnon-overlapping(ortheintergeniclncRNA;lincRNAs),ortheoverlappinglncRNAs,whichincludeintronicandantisense(AS)lncRNAs.IntroniclncRNAsaretranscribedwithintheintronofaprotein-codinggene,andthereforedonotcontainsequencescomplementarytothemature,splicedmRNAoftheprotein-codinggene.AntisenselncRNA,however,containsregion(s)ofcomplementarysequenceswiththemature,splicedmRNAoftheoverlappingprotein-codinggene.Examplesofimmune-relatedlncRNAsfromthedifferentlncRNAsub-classesareprovided.Abbreviations:miRNA,micro-RNA;ncRNA,non-codingRNA;snRNA,smallnuclearRNA;snoRNA,smallnucleolarRNA.lncRNAsdoproducesmallproteins(orpeptides)whichmaymediateadditionalfunctions.BecausethelncRNA?eldisrapidlyevolving,aclearnomenclaturefortheseRNAsisbadlyneeded(Figure1).Commonlyusedterms,suchaslongintergenicnon-codingRNAs(lincRNA),refertolncRNAsthatarestrictlyintergenicanddonotoverlapwithknownprotein-codinggenes.AllotherformsoflncRNAsareeithertranscribedwithin(e.g.,introniclncRNA),orexhibitsomeoverlapwithaknownprotein-codinggene(e.g.,antisenselncRNA).Antisense(AS)lncRNAsareparticularlyinterest-ingbecausetheyappeartobethemajorlncRNAsubtype:itisestimatedthatupto72%ofmurinegenomiclocishowevidenceoftranscription[19].AgrowingbodyofevidenceindicatesthatlncRNAsplayanimportantroleinthetranscriptionalandpost-tran-scriptionalregulationofgeneexpressioninavarietyofbiologicalprocessessuchasX-chromosomeinactivation(Xist/Tsix)[20,21],genomicimprinting(H19andAir)[22,23],stemcellpluripotency[24],development[25],cancermetastasis(HOTAIR)[26],andatherosclerosis(Anril)[27].AfunctionalroleoflncRNAshasalsostartedtoemergeincontrollinggeneexpressionintheimmunesystem.lncRNAsarewidelyexpressedinimmunecellsincludingmonocytes,macrophages,dendriticcells(DC),neutrophils,Tcells,andBcellsduringtheirdevelopment,differentiation,and/oractivation.However,thefunctionsoftheseRNAsareonlybeginningtobecharacterized.ExpressionandtheroleoflncRNAsinimmunecelldevelopmentAnemergingthemeinthebiologyoflncRNAsistheirroleincellandtissuedevelopment[28].ThisishighlightedbyalargebodyofevidenceindicatingthatlncRNAsplaykeyrolesduringthedevelopmentoferythrocytes[29,30],adi-pocytes[31],cardiomyocytes[32],epidermalcells[33],andstemcells[24],amongothers.Arecentstudyillustratesa624similarfunctionalroleforlncRNAsincontrollingthedifferentiationofhumanmonocytesintodendriticcells(DC)[34].DCsactastheprimaryantigen-presentingcells(APCs)forTcellsandbridgetheinnateandadaptivearmsoftheimmunesystem[35].DCscomeintwo?avors:(i)conventionalDCs(cDCs;alsoknownasmyeloidDCs),whichfunctionasAPCsandproducersofinterleukin12(IL-12);and(ii)plasmacytoidDCs(pDCs)thatproduceabundantlevelsoftypeIinterferon(IFN)followingbacte-rialandviralinfections[36].ToidentifylncRNAsinvolvedinDCmaturationandfunction,thehumantranscriptomewaspro?ledusingRNA-seqatdifferentstagesofmonocytedifferentiationintoDCsinvitro[34].Thisapproachiden-ti?edacohortoflncRNAsthatweredifferentiallyexpressedduringthemonocytetoDCtransition.DetailedstudyofoneoftheseRNAs,anintergeniclncRNAwhichtheauthorsnamedlnc-DC,showedthatitwasexpressedexclusivelyinDCs.Furthermore,lnc-DCwasshowntoberequiredforthedifferentiationofhumanmonocytesintoDCsinvitro,andplayedasimilarroleinmice.Expressionoflnc-DCwasdrivenbyPU.1,akeytranscriptionfactorrequiredfortheDCmaturationprogram[37].InadditiontocontrollingthematurationofDCs,lnc-DCalsocontrolstheexpressionofseveralDCgenesincludingCD40,CD80,andHLA-DR.Therefore,lnc-DCcontrolstheuptakeofantigensbyDCs,thesubsequentinductionofallogenicCD4+Tcellproliferation,andcytokineproduction[34].Lnc-DCmediatestheseeffectsbybindingthetran-scriptionfactorSTAT3(signaltransducerandactivatoroftranscription3)inthecytosol,preventingSTAT3bindingto,anditsdephosphorylationby,thetyrosinephosphataseSHP1(Srchomologyregion2domain-containingphospha-tase-1).TheseeventsenhanceSTAT3phosphorylationontyrosine-705.Themolecularactionoflnc-DCinthecytosolappearstobeanalogoustoanotherlncRNA,nuclearre-pressorofNFAT(NRON),thatsequestersthetranscrip-tionfactorNFAT(nuclearfactorofactivatedTcells)intoaninactiveRNACproteinscaffoldinthecytosolofTcells[38].Anotherinterestingaspectoflnc-DCisitsuniqueandabundantexpressionincDC(around100-foldhigherthaninpDCsorinanyotherimmunecelltype)suggestingthatitcanbeutilizedasaspeci?candsensitivemarkerofconventionalDCsinthehematopoieticsystem.HOXantisenseintergenicRNAmyeloid1(HOTAIRM1)isencodedinthehumanHOXAgeneclusterandislinkedtothematurationofgranulocytes[39].HOTAIRM1expressionisrestrictedtomyeloidcells,andisupregulatedduringretinoicacid(RA)-inducedgranulocytedifferentiationofpromyelocyticNB4leukemia,andnormalhumanhemato-poieticstemcells.KnockdownofHOTAIRM1bluntsRA-inducedexpressionofneighboringgenesHOXA1andHOXA2(butnotdistalHOXAgenes)aswellasmyeloiddifferentiation-associatedgenesCD11bandCD18.BecauseHOXAgenesareinvolvedinthetranscriptionalregulationofnormalhematopoiesis[40]andacutemyeloidleukemia(AML)[41,42],ithasbeenproposedthatHOTAIRM1playsanimportantroleinmyelopoiesisbyregulatingHOXAgeneexpressionincis.Together,thesestudiesillustratetheimportanceoflncRNAsincontrollingthedevelopmentofimmunecells.ItremainstobeseenwhetherotherimmunecelltypessuchasmonocyteCmacrophages,innatelymphoidTrendsinMolecularMedicineNovember2014,Vol.20,No.11cells(ILC),Bcells,andTcellsubsets(Th1,Th2,Th17,andTreg)alsoexpresslncRNAsthatcontroltheirdevelopment.FunctionallncRNAsintheinnateimmunesystemInnateimmunityisthe?rstlineofdefenseagainstmicro-bialpathogens.RecentstudiescollectivelyindicatethatlncRNAsplayimportantfunctionalrolesininnateimmunecellssuchasphagocytes.Notably,thediscoveryoflincRNA-Cox2[43],Lethe[44],PACER[45]andTHRIL(TNFaregulatinghnRNPLinteractinglncRNA)[46]rep-resentexcitingexamplesofthegrowinglistoflncRNAsthathavebeenimplicatedincontrollinggeneexpressioninimmunecells.Transcriptomepro?ling(RNA-seq)inmousebonemar-row-derivedmacrophages(BMDM)ledtotheidenti?cationof72lncRNAsthatweresigni?cantlyupregulatedinmacrophagesexposedtothesyntheticbacteriallipoproteinPam3CSK4,whichsignalsviaToll-likereceptor2(TLR2)[43].OneofmostrobustlyinducedlncRNAs,lincRNA-Cox2,wasshowntoactasaregulatoroftheTLRinducedtranscriptionalprograminmacrophages.ThegeneforlincRNA-Cox2,earlieridenti?edasanintergenictran-scriptinthecatalogoflincRNAsreportedbyGuttmanetal.[6],islocated??51kbfromthe30endoftheprosta-glandin-endoperoxidesynthase2(Ptgs2;Cox2)geneontheoppositestrandofchromosome1.LincRNA-Cox2washighlyinducedbymultiplein?ammatorytriggers,includ-ingTLRligands[lipopolysaccharide(LPS)andPam3CSK4]andmicrobialpathogens(ListeriamonocytogenesandSen-daivirus)byapathwayinvolvingMyD88(myeloiddiffer-entiationprimaryresponsegene88)andthetranscriptionfactorNF-kB(nuclearfactorklight-chain-enhancerofactivatedBcells)[43].Functionally,lincRNA-Cox2appearstoactivateandrepressexpressionofdistinctclassesofimmunegenes.Inrestingmacrophages,lincRNA-Cox2repressestheexpressionof??700genesincludingchemokines(Ccl5andCx3cl1)andinterferon-stimulatedgenes(ISG)(Irf7,Isg15,I?204,andOas2),whereasitwasrequiredfortheinducibleexpressionofseveralothergenes(IL6,Tlr1,andIL23a)turnedonbytheTLR2pathway.lincRNA-Cox2physicallyinteractswithRNA-bindingproteins(RBP)hnRNP-A2/B1andhnRNP-A/Btomediateitsrepressivefunctions.Interestingly,thesetwohnRNPsarenotinvolvedinmediatingtheactivatingfunctionsofthislincRNA,suggestingthatadditionallincRNA-Cox2interactingprotein(s)remaintobeidenti-?ed.HowlincRNA-Cox2contributestoTLR2-inducedex-pressionofIL6andothergenesiscurrentlyunknown.Futurein-depthstudiesinanimalslackinglincRNA-Cox2willshedlightontheinvivoimmunefunctionsofthisRNA.ThegenomiclocuscontainingPtgs2(Cox2)containstwoknownlncRNAgenes(lincRNA-Cox2,andCox2-divergent(Ptgs2Ptgs2os))inmice[43,44],andtherecentlydescribedlncRNAgenePACERinhumans[45].TheCox2-divergentlncRNAislocatedatthe50-endofPtgs2(non-overlapping),andistranscribedfromtheopposite(negative)DNAstrand[44].AlthoughfunctionsofCox2-divergentareunclear,itishighlyinducedinmouseembryonic?broblasts(MEF)exposedtotumornecrosisfactora(TNFa),andLPS,inanNF-kB-independent625manner[44].ThelncRNAPACER(p50-associatedCOX-2extragenicRNA)isexclusivelyinvolvedincontrollingtheexpressionofCOX-2incisinhumanmonocyteCmacro-phagecelllines,andprimaryhumanmammaryepithelialcells[45].PACERexpressionisregulatedbythechroma-tin-boundary/insulatorfactorCCCTC-bindingfactor(CTCF),whichestablishesanopenchromatindomainintheupstreamregionofCOX2topromotePACERexpres-sion.Inturn,PACERbindstotheNF-kBhomodimerp50/p50(atranscriptionalrepressorcomplex)andtitratesitawayfromtheCOX2promoter.TheseeventsthenfavortherecruitmentoftheactiveNF-kBheterodimerp65/p50,whichpromotestheassemblyofthetranscriptionpreini-tiationcomplexcontaininghistoneacetyltransferasep300andRNApolymeraseIIattheCOX2promoter.Therefore,PACERappearstofunctionbyoccludingtherepressorcomplex(p50/p50)tofacilitatetheexpressionofPtgs2/COX2.ThisisremarkablysimilartothelincRNAJpx,whichactivatestheexpressionofXistduringtheinitiationofX-chromosomeinactivationbyevictingCTCFfromtheXistpromoter[47].Lethe,afunctionalpseudogene(Rps15a-ps4)lncRNA,isalsohighlyinducibleinMEFstreatedwiththeNF-kB-activatingin?ammatorytriggersTNFaandIL-1b[44].Le-theexpressionisalsoinducedinresponsetotheanti-in?ammatoryglucocorticoidreceptoragonist,dexameth-asone[44].LetheattenuatestheNF-kB-dependentin-?ammatoryresponseinMEFsbyphysicallybindingtop65(RelA),whichinhibitsRelAoccupancyatthepromoteroftargetgenes,includingIL6,IL8,andsuperoxidedis-mutase2(SOD2)[44].Consistentwiththismodel,Letheisprimarilylocalizedtochromatin.Interestingly,Letheexpressioninthespleenofagedmiceismarkedlylower(20C50-fold)thaninyoungmice,suggestingafunctionallinkbetweendecreasedLetheexpressionandenhancedNF-kBsignalingassociatedwithageing[44].Lethethere-forefunctionsasafeedbackregulatoroftheNF-kBsig-nalingpathwaytocontrolthein?ammatoryresponse.Inaddition,Lethehasprovidedthe?rstevidencefortheexistenceofafunctionalpseudogenelncRNA,raisingthepossibilitythatmanymorecurrentlyannotatedpseu-dogenesinthemammaliangenomecouldinfactbefunc-tional(lncRNA)genes.THRILisanotherimmune-relatedlncRNA,whichpri-marilycontrolstheexpressionofTNFainthehumanmonocyte-likeTHP-1cellline[46].THRILwasidenti?edasoneof159lincRNAsthatweredifferentiallyexpressed(80%down,20%up)inPam3CSK4-treatedTHP-1cells[46].LentiviralshorthairpinRNA(shRNA)-mediatedknockdownofapoolofninelincRNAsincludingTHRILresultedinimpairedTNFaand/orIL-6production,sug-gestingthatseveralTLR2-inducedlincRNAscouldcooper-atetoregulatein?ammatoryresponsesinhumanmonocytes[46].RNA-seqfollowingshRNA-silencingofTHRILexpressioninTHP-1cellsrevealeddifferentialexpressionof319genesinresponsetoPam3CSK4,indicat-ingthatTHRILregulatesabroadpanelofimmunegenes[46].THRILinteractswithhnRNPLtocontrolTNFaexpression,andbothTHRILandhnRNPLlocalizetotheTNFApromoter[46].BecausetheexpressionofTHRILisinhibitedbyTNFa,itappearstoactasanegativefeedback626TrendsinMolecularMedicineNovember2014,Vol.20,No.11regulatorofTNFaexpressioninhumanmonocytes.THRILexpressionissigni?cantlyreducedduringtheacutestageofthein?ammation-associatedKawasakidisease[46];thebiologicalsigni?canceofthisdiseaseassociationhoweverremainsunclear.Morerecently,thenuclearenrichedabundanttran-script1(NEAT1),akeyplayercontrollingtheformationofheterochromatinstructuresknownas‘paraspeckles’[48],hasbeenlinkedtotheexpressionofthecytokineIL-8inhumancelllinesfollowingviralinfections(HSV-1andin?uenzaAvirus),orTLR3-activationbydsRNA[49].NEAT1relocatestherepressorSFPQ(splicingfactorprolineglutamine-rich),aNEAT1-bindingparaspeckleprotein,fromtheIL8promotertothenuclearparaspecklebody,tomediateIL8transcription[49].Inaddition,NEAT1alsoregulatesHIV-1bypromotingtheexportofHIV-1mRNAfromthenucleustothecytoplasm[50].Col-lectively,thesestudieshighlighttheemergenceoflncRNAsasanimportantregulatorylayerincontrollinggeneexpressionininnateimmunity.lncRNAsinadaptiveimmunityLymphocytes(TandBcells)aretheprimarycellularmediatorsoftheadaptiveimmunesystem.ThereisnowclearevidencethatlymphocytesexpressmanylncRNAs,andthattheseplaycrucialrolesindevelopment,lineage-speci?cdifferentiation,andactivation.TwolncRNAsexpressedinTcells,NTT(non-codingtranscriptinCD4+Tcells)[51]andNRON[52],representtheearliestlncRNAgenesidenti?edinimmunecells.NTTisa17kbpolyade-nylated,unsplicedintergenictranscriptlocalizedtothenucleus.NTTisprimarilyexpressedinactivatedhumanCD4+Thowever,itsfunctionremainstobede?ned.ApotentialfunctionallinkbetweenNTTandtheIFN-greceptor(IFNGR)geneisoneaspectthatwarrantsfurtherinvestigationbecausethesegenessharethesamegenomiclocus(6q23Cq24),andtheyexhibitsimilarspatiotemporalexpressionduringTcellactivation[51].NRON,anintroniclncRNA,wasidenti?edinhumanTcellsasaresultofanshRNAscreenexploringtheroleof512evolutionarilyconservedncRNAsthatwereknownatthetime[52].NRONwasfoundtoregulateNFAT,aCa2+-activatedtranscriptionfactor,andmodulatetheexpres-sionofIL-2inactivatedTcells.NRONinterfereswiththenucleartransportofNFAT(andnotthetranscriptionalactivity)byinteractingwithmembersoftheimportin-bsuperfamily,(includingthenucleartransportfactorKPNB1)[52]whichpromotethenucleocytoplasmictrans-portofcargossuchasNFAT[53].SubsequentstudieshoweverhaveshownthatNRONactsasastructuralscaffoldlncRNAtosequesterinactive,phosphorylatedNFATintoalargecytosolicproteinCRNAcomplexcontain-ingNFAT,IQGAP(IQmotif-containingGTPaseactivatingprotein),andseveralNFATkinases[38].Additionalstud-iesareneededtoreconciletheseseeminglydisparatemodesofNRON-mediatedcontrolofNFATresponses.Nonetheless,NRONappearstoplayacrucialfunctionincontrollingNFAT-dependentIL-2expressioninTcells.NRONexpressionisenrichedinlymphoidtissue,consis-tentwithitsrolesinmodulatingNFATactivityinTcells[52].The?rstsystematicstudyaimedatpro?lingthelncRNAtranscriptomeinCD8+TcellswasperformedbyPangetal.andledtotheidenti?cationofhundredsoflncRNAsinthemousegenome,manyofwhichwerelymphoidcellspeci?canddifferentiallyexpressedinna-¨?ve,memory,oreffectorCD8+Tcells[1].Morerecently,genome-widetranscriptionalpro?lingofmurineTcellshasidenti?ed1524lincRNAgeneclustersacrossapanelofTcellsubsets,fromearlyprogenitorstoterminallydifferentiatedhelperTcells[54].TheselincRNAsexhib-iteddynamic,cell-andactivationstate-speci?cexpres-sion.DuringCD4+TcelldifferentiationintoTh1andTh2cells,expressionoflincRNAsintheseTcellsubsetswasdrivenbytheTcelllineage-speci?ctranscriptionfactors,T-betandStat4forTh1cells,andStat6andGata3forTh2cells.OneTh2-speci?clincRNA,lincR-Ccr2-50AS,islocatedupstreamofthechemokinereceptorCcr2gene,andistranscribedintheantisense(AS)direction[54].LincR-Ccr2-50AS,togetherwithGata3,controlstheexpressionofimmunegenesinTh2cells.ThislincRNAalsocontrolsthemigrationofTh2cellstothelungsinvivo,presumablybycontrollingtheexpressionofseveralche-mokinereceptorgenes(Ccr1,Ccr3,Ccr2,andCcr5),whicharealllocatedinthesamegenomiclocusaslincR-Ccr2-50AS[54].ThemoleculardetailsofhowlincR-Ccr2-50ASmediatestheexpressionofthesegenesremainsunclear.Inaddition,manyotherlincRNAsarealsospeci?callyexpressedineachoftheCD4+Tcellsubsets:na?¨vecells(79),Th1(101),Th2(63),Th17(27),andinducedregulatoryTcells(iTreg)(37)[54].However,whatfractionoftheselincRNAsarefunctionallylinkedtoTcelldevelopment,aswellastheireffectorfunctions,remaintobeinvestigated.AnotherlincRNAexpressedinhumanTcells,GAS5(growtharrest-speci?ctranscript5),hasbeenlinkedtocellcyclearrestinresponsetoeithernutrientdeprivationorexposuretothemammaliantargetofrapamycin(mTOR)antagonist[55C57].Bcells,mediatorsoftheantibody-dependenthumoralarmoftheadaptiveimmunity,alsoexpresslncRNAs.TheantisenselncRNAFas-AS1(FASantisensetranscript1)tightlycontrolstheproductionofsolubleFasreceptor(sFas),whichbindsFasligandtoregulateFas-inducedapoptosisinBcelllymphomas[58].Fas-AS1bindstothesplicingfactorRBM5toinhibitRBM5-mediatedalterna-tiveskippingoftheexon6ofFas(alsoknownasCD95;TNFRSF6),whichisrequiredtogeneratethesFasmRNA.BecauseserumsFaslevelsareassociatedwithpoorprog-nosisinnon-Hodgkin’slymphoma[59],theFas-AS1lncRNAisapotentialtherapeutictargetinthissetting.Inaddition,widespreadantisenseintergenictranscriptionhasbeenshowntooccurinthevariable(V)regionoftheimmunoglobulinheavychain(Igh)locusinBcells,whichispotentiallylinkedtochromatinremodelingassociatedwithV(D)JrecombinationinvolvedintheproductionofthediverserepertoireofantigenicreceptorsindevelopingBcells[60,61].WhetherlncRNAsalsoplayaroleinthematurationandeffectorfunctionofBcellsremainsanopenquestion.Collectively,however,thesestudiesdem-onstratethatimmunecellsexpressavastrepertoireoflncRNAs,manyofwhichareexpectedtoplaykeyrolesinthehostimmuneresponse.TrendsinMolecularMedicineNovember2014,Vol.20,No.11RoleoflncRNAsinhostdefenseagainstmicrobialinfectionAfunctionalroleforlncRNAsincontrollingthehostim-muneresponseduringmicrobialinfectionhasalsoemerged.ThisisbesthighlightedbythediscoveryofalincRNAtermedNeST[62](originallyidenti?edasTmevpg1[63]),acandidategenecontrollingthepersis-tenceofTheiler’svirusinthecentralnervoussysteminmice.Inarecentstudyemployinginter-crossesbetweensusceptibleSJL/Jmice(thesemiceexpressNeST,developpersistentTheiler’svirusinfection,andclearSalmonellainfection),andtheresistantB10.Sstrain(lackNeSTex-pression,clearTheiler’svirusinfection,andsuccumbtoSalmonellainfection),aswellasthroughthegenerationofB10.SmiceexpressingaNeSTtransgene,Gomezetal.haveprovidedcompellinggeneticevidencethatNeSTisthehostfactorresponsibleforthepersistenceofTheiler’svirusaswellasfortheclearanceofSalmonellainfectioninmice[62].Nestispositionednear,andconvergentlytran-scribedtotheIfnggene.NeSTisselectivelyexpressedinCD4+Th1(butnotTh2)cells,CD8+Tcellsandnaturalkiller(NK)cells[62C64].ThetranscriptionfactorsT-betandStat4,whichareknowntodrivenaiveCD4+TcelldifferentiationintoTh1cells,controltheexpressionofNeST[64].NeSTbindstoWDR5(WDrepeat-containingprotein5),acomponentofthehistonemethyltransferasecomplex,tomediatehistone3lysine4trimethylation(H3K4me3)attheIfngpromotertopromoteIFN-gexpres-sioninCD8+Tcells[62].BecauseNestandIfngarelocatedinthesamegenomiclocus,NeSTisthoughttoactincisasanenhancerRNAtopromoteIfngexpression.NeSTalone,however,isnotsuf?cienttodriveIfngexpressionbecauseitworkscooperativelywiththetranscriptionfactorT-bet[64].ItisnoteworthythatNeST,whichisexpressedatverylowlevels(??0.15copiespercell)inCD8+Tcells,mediatessuchprofoundeffectsuponIFN-gproduction.ThecrucialroleofNeSTindeterminingthehostsuscepti-bilitytoaninfectiousdiseasefurtherhighlightstheimpor-tanceoflncRNAgenesintheimmunesystem.HundredsoflncRNAsarealsoexpressedinvivofollowinginfectionwithcoronavirus(thecausativeagentofacuterespiratorysyn-drome)orin?uenzavirus[65].Thefunctionalimportanceofthesevirus-inducedlncRNAs,however,ispresentlyunknown.Inadditiontohost-encodedlncRNAs,severalmicrobialspeciesalsoexpresslncRNAs,whichinsomecasessubverthostimmunity[66].Severalstudieshavehighlightedafunctionalroleforanon-codingpolyadenylatednuclear(PAN)RNAencodedintheKaposi’ssarcoma-associatedherpesvirus(KSHV)genome[67].TheKSHVPANlncRNAfacilitatestheconversionoflatenttolytic(active)infection,presumablybyregulatingthedissociationofLANA(laten-cyassociatednuclearantigen)fromtheKSHVgenome[68].Inaddition,thePANlncRNArecruitsthedemethy-laseJMJD3andUTXtoepigeneticallyrepressedregionsoftheKSHVgenometoenhanceviralgenomeexpression[69].TheKSHVPANlncRNAalsosuppressesantiviralhostfactorsincludingIFN-a,IFN-g,andRNaseLthroughitsinteractionwiththepolycombrepressivecomplex2(PRC2)tosubverthostimmunityandpromoteviralrepli-cationininfectedcells[67,70].Similarly,theherpesvirus627包含各类专业文献、高等教育、文学作品欣赏、幼儿教育、小学教育、专业论文、外语学习资料、Long 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