《计算系统生物学导论》系统生物学导论

TheIntroductionofComputationalSystemsBiology计算系统生物学导论WangDongAssociateProfessorEmail:wangdong,WhatisnoncodingRNA?,Non-codingRNA(ncRNA)isaRNAmoleculethatfunctionswithoutbeingtranslatedintoaprotein,HowmanyRNAsincells?,non-codingRNA(20-20000nt),RNA,mRNA,smallnon-codingRNA(sncRNA)(20-200nt),longnon-codingRNA(lncRNA)(200),Non-codingRNA:Versatilityinformandfunction,NoncodingRNAgenesaresurprisinglynumerous.,NoncodingRNAhaveaverydifferentfunctions.,TimeforRNomics,PNAS,97(26):14035-14037,Dec19,2000,UnderstandingRNomicsfromanexpendingsnoRNAworld,CouzinJ.Breakthroughoftheyear.SmallRNAsmakebigsplash.Science.2002Dec20;298(5602):2296-7.,DNARNAProtein,Genomics,Proteomics,Studynon-codingRNAsonthegenomicscale,RNomics,Studytheidentification,expression,biogenesis,structure,regulationofexpression,targets,andbiologicalfunctionsofnoncodingRNAsonthegenomicscale.,ahidden“RNAworld”withinmodernDNAworld,Novelclassesofnon-codingRNAsandcancer,SummarizenewlydiscoveredclassesofncRNAs,highlighttheirfunctioningincancerbiologyandpotentialusageasbiomarkersortherapeutictargets,Group:basedontranscriptsize,SmallncRNAs,LongncRNAs,Smallnon-codingRNAs,Smallnon-codingRNAs,microRNA,MicroRNAs,accountfor12%ofthehumangenomeandcontroltheactivityof50%ofallprotein-codinggenes,betranscribedfromtheirownpromotersandthatmiRNAsaregeneratedbyRNApolymeraseII(RNAPII)asprimarytranscripts(pri-miRNAs),Inthecytoplasm,thepre-miRNAsareprocessedtomaturemiRNA,characteristic,MicroRNAs,miRNAtargetinginmammaliancellsoccurspredominantlythroughbindingtosequenceswithin3UTRs,howeverinhibitionofgeneexpressionthroughtargetingthe5UTR,regulatecrucialcellprocessessuchasproliferation,differentiation,andapoptosis,cancerswheremiRNAshavebeenfoundtobealsosignificantprognosticandpredictivemarkers,function,PiwiproteinsassociatedRNAs,BindPiWiproteins;Dicer-independentmechanism;derivedfromcomplexDNAsequenceelements;,germcelldevelopmentstemcellself-renewalretrotransposonsilencing,SmallnucleolarRNAs,enrichedinthenucleoluslocatedwithinintronsofprotein-codinggenesandaretranscribedbyRNApolymeraseII,source,SmallnucleolarRNAs,haveimportantfunctionsinthematurationofothernoncodingRNAs,managepost-transcriptionalmodificationofrRNAandsnRNAcellulartargetmRNA,whoseactivityisregulatedbysnoRNA,snoRNAsarecriticallyassociatedwiththedevelopmentandprogressionofcancer,Longnon-codingRNAs,Longnon-codingRNAs,ManyidentifiedlncRNAaretranscribedbyRNApolymeraseIIlikelytobetranscribedbypolymeraseIII,source,Longnon-codingRNAs,alternativesplicingmodulationofproteinactivityalternationofproteinlocalizationepigeneticregulationprecursorsofsmallRNAsandeventoolsformiRNAssilencingregulatorsofprotein-codinggeneexpression,processes,Longnon-codingRNAs,fourdifferentmechanismsoflncRNAsaction,lncRNAscanfunctionassignalsandregulategeneexpressionAsSignals,lncRNAexpressioncanfaithfullyreflectthecombinatorialactionsoftranscriptionfactors(coloredovals)orsignalingpathwaystoindicategeneregulationinspaceandtime.,Longnon-codingRNAs,AsDecoys,lncRNAscantitrateawaytranscriptionfactorsandotherproteinsawayfromchromatin,ortitratetheproteinfactorsintonuclearsubdomains.AfurtherexampleofdecoysislncRNAdecoyformiRNAtargetsitesSpecifically,the3UTRofPTENP1RNAwasfoundtobindthesamesetofregulatorymiRNAsequencesthatnormallytargetthetumor-suppressorgenePTEN,reducingthedownregulationofPTENmRNAandallowingitstranslationintothetumor-suppressorproteinPTEN,Longnon-codingRNAs,lncRNAscanrecruitchromatin-modifyingenzymestotargetgenesandthereforefunctionasguides.lncRNAscanrecruitchromatinmodifyingenzymestotargetgenes,eitherincis(nearthesiteoflncRNAproduction)orintranstodistanttargetgenes.,lncRNAscanbringtogethermultipleproteinstoformribonucleoproteincomplexeslncRNAscanbringtogethermultipleproteinstoformribonucleoproteincomplexes.ThelncRNA-RNPmayactonchromatinasillustratedtoaffecthistonemodifications.Inotherinstances,thelncRNAscaffoldisstructuralandstabilizesnuclearstructuresorsignalingcomplexes,LongintergenicnoncodingRNAs,liewithinthegenomicintervalsbetweentwogenes,lncRNAscouldbeutilizedforcancerdiagnosis,prognosis,andserveaspotentialtherapeutictargets,involvedintumorigenesisandcancermetastasisandimprinting,processes,function,LongintronicnoncodingRNAs,characteristic,Liewithintheintronsevolutionaryconservedtissueandsubcellularexpressionspecificity,function,LongintronicnoncodingRNAs,aberrantlyexpressedinhumancancerspossiblelinkwithposttranscriptionalgenesilencing,LongncRNAswithdualfunctions,characteristic,protein-codingFunctionallyregulatoryRNAcapacity,deregulationinbreastandovariantumorsmodulategeneexpressionthroughdiversemechanisms,Conclusionsandfutureperspectives,SmallncRNAsareinvolvedmainlyinthepost-transcriptionalgeneregulationusingtranslationalrepressionorRNAipathwayLongncRNAsaremuchmoreinvolvedinepigeneticregulationdifferentialexpressionofncRNAsisbecomingrecognizedasaoneofthehallmarksofcancercellncRNAshavethepromisingpotentialintargetedregulationofgeneexpressionand,therefore,incancertargetedtherapy,TheGENCODEv7catalogofhumanlongnoncodingRNAs:Analysisoftheirgenestructure,evolution,andexpression,TheselncRNAscanbeenfurtherreclassifiedintothefollowinglocusbiotypesbasedontheirlocationwithrespecttoprotein-codinggenes1.AntisenseRNAs：whichhavetranscriptsthatintersectanyexonofaprotein-codinglocusontheoppositestrand,orpublishedevidenceofantisenseregulationofacodinggene（3233）,2.LincRNA：transcriptsthatareintergenicnoncodingRNAlociwithalength200bp（5094）3.overlappingtranscripts:containacodinggenewithinanintrononthesamestrand(unknow)4.intronictranscripts:residewithinintronsofacodinggene,butdonotintersectanyexons(378),Intergenic,thensubclassifiedaccordingtoitstranscriptionorientationwiththeclosestprotein-codinggene(samesense,convergent,ordivergent).,LncRNAsdonotshowevidenceofprotein-codingpotential,LncRNAsshowlowerandmoretissue-specificexpressionthanprotein-codinggeneslncRNAsshowlowerexpressioninalltissuescomparedwithmRNAsalthoughlncRNAsshowrelativelyhighexpressionintestis,LncRNAsalsoshowmoretissue-specificpatternscomparedwithprotein-codinggenesThemajority(65%)ofprotein-codinggenesweredetectedinallHBMtissuescomparedwith11%oflncRNAs(21%oflncRNAswerenotbedetectedinanytissue,and11%areonlydetectedinasingletissue),Almost40%(3934lncRNAgenes,5361transcripts)ofGENCODElncRNAsintersectprotein-codinggeneloci,anditispossiblethatsuchlncRNAssomehowcontributetotheregulationofthelatter(Fig.1B;Gingeras2007;Pasmantetal.2011).WethereforecomputedcorrelationsofexpressionbetweentheselncRNAgenesandtheirhostmRNAs,CorrelationofexpressionbetweenoverlappinglncRNAsandmRNAs,WefoundthatlncRNAshavemorepositivecorrelationswithintersectingmRNAselementsthanexpectedbychance,ThereismountingevidencethatmanylncRNAsarerecruitedtochromatinandepigeneticallyregulategeneexpressionThus,wewouldexpectthatlncRNAsshouldbepreferentiallylocalizedinthechromatinandnuclearRNAfractions,incontrasttoprotein-codingmRNAsthataretraffickedtothecytoplasmfortranslation,LncRNAsareenrichedinthenucleus,Inallcelllines,exceptforNHEK,weobservedarobustandhighlystatisticallysignificantenrichmentoflncRNAsinthenucleus,comparedwithprotein-codingmRNAs.Furthermore,thelncRNAsnuclear/cytoplasmicenrichmentisconsistentbetweencelltypes,WealsotestedwhetherparticularclassesoflncRNAintergenic,intronic,antisensehaddistinctnuclearlocalizationpropensities,butwecouldfindnosignificantdifference,suggestingthatnuclearenrichmentisageneralpropertyoflongnon-protein-codingtranscriptsWealsotestedwhetherparticularclassesoflncRNAintergenic,intronic,antisensehaddistinctnuclearlocalizationpropensities,butwecouldfindnosignificantdifference,suggestingthatnuclearenrichmentisageneralpropertyoflongnon-protein-codingtranscripts,WefurtherinvestigatedwhetherlncRNAsareenrichedinparticularcompartmentswithinthenucleus（chromatin）.LncRNAsaresignificantlymoreenrichedinchromatinthanmRNAs:Themedianchromatin/nucleusexpressionratioforlncRNAsismorethantwicethatofmRNAs(0.55vs.0.26,respectively).ThislendsfurthersupporttotheideathatlncRNAsarespecificallyrecruitedtochromatin,wheretheyplayaregulatory,LongnoncodingRNAsarerarelytranslatedintwohumancelllines,Introductions,AparticularlyintriguingpropertyofmammalianlncRNAsistheirlackofevolutionaryconservation,relativetoprotein-codinggenes.Itisimportanceofusingempiricalmethodologiestodocumentwhetherl