《计算系统生物学导论》系统生物学导论.ppt

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1、TheIntroductionofComputationalSystemsBiology计算系统生物学导论计算系统生物学导论WangDongAssociateProfessorEmail:WhatisnoncodingRNA?Non-coding RNA(ncRNA)is a RNA molecule that functions without being translated into a proteinHowmanyRNAsincells?mRNA rRNA tRNAProteinsnRNAsnoRNAgRNA Antisense RNASRP-RNAmicroRNApRNARibozy

2、meTelomerase RNA?non-coding RNA (20-20000nt)RNAmRNAsmall non-coding RNA(sncRNA)(20-200nt)long non-coding RNA(lncRNA)(200)Non-coding RNA:Versatility in form and functionNoncodingRNAgenesaresurprisinglynumerous.NoncodingRNAhaveaverydifferentfunctions.Time for RNomicsPNAS,97(26):14035-14037,Dec 19,2000

3、Understanding RNomics from an expending snoRNA worldCouzin J.Breakthrough of the year.Small RNAs make big splash.Science.2002 Dec 20;298(5602):2296-7.DNA RNA ProteinStudy non-coding RNAs on the genomic scale Study the identification,expression,biogenesis,structure,regulation of expression,targets,an

4、d biological functions of noncoding RNAs on the genomic scale.a hidden“RNA world”within modern DNA worldNovelclassesofnon-codingRNAsandcancerSummarize newly discovered classes of ncRNAs highlight their functioning in cancer biology and potential usage as biomarkers or therapeutic targetsGroup:based

5、on transcript sizeSmall ncRNAs Long ncRNAsSmallnon-codingRNAsSmall non-coding RNAsmicroRNAMicroRNAs account for 12%of the human genome and control the activity of 50%of all protein-coding genes be transcribed from their own promoters and that miRNAs are generated by RNA polymerase II(RNAPII)as prima

6、ry transcripts(pri-miRNAs)In the cytoplasm,the pre-miRNAs are processed to mature miRNAcharacteristicMicroRNAs miRNA targeting in mammalian cells occurs predominantly through binding to sequences within 3UTRs,however inhibition of gene expression through targeting the 5UTR regulate crucial cell proc

7、esses such as proliferation,differentiation,and apoptosis cancers where miRNAs have been found to be also significant prognostic and predictive markersfunctionPiwi proteins associated RNAs Bind PiWi proteins;Dicer-independent mechanism;derived from complex DNA sequence elements;germ cell development

8、 stem cell self-renewal retrotransposon silencingSmallnucleolarRNAs enriched in the nucleolus located within introns of protein-coding genes and aretranscribed by RNA polymerase IIsourceSmallnucleolarRNAs have important functions in the maturation of other noncoding RNAs manage post-transcriptional

9、modification of rRNA and snRNA cellular target mRNA,whose activity is regulated by snoRNA snoRNAs are critically associated with the development and progression of cancerLongnon-codingRNAsLongnon-codingRNAs Many identified lncRNA are transcribed by RNA polymerase II likely to be transcribed by polym

10、erase IIIsourceLongnon-codingRNAs alternative splicing modulation of protein activity alternation of protein localization epigenetic regulation precursors of small RNAs and even tools for miRNAs silencingregulators of protein-coding gene expressionprocessesLongnon-codingRNAsfourdifferentmechanismsof

11、lncRNAsactionlncRNAscanfunctionassignalsandregulategeneexpressionAsSignals,lncRNAexpressioncanfaithfullyreflectthecombinatorialactionsoftranscriptionfactors(coloredovals)orsignalingpathwaystoindicategeneregulationinspaceandtime.Longnon-codingRNAsAsDecoys,lncRNAscantitrateawaytranscriptionfactorsando

12、therproteinsawayfromchromatin,ortitratetheproteinfactorsintonuclearsubdomains.AfurtherexampleofdecoysislncRNAdecoyformiRNAtargetsitesSpecifically,the3UTRofPTENP1RNAwasfoundtobindthesamesetofregulatorymiRNAsequencesthatnormallytargetthetumor-suppressorgenePTEN,reducingthedownregulationofPTENmRNAandal

13、lowingitstranslationintothetumor-suppressorproteinPTENLongnon-codingRNAslncRNAscanrecruitchromatin-modifyingenzymestotargetgenesandthereforefunctionasguides.lncRNAscanrecruitchromatinmodifyingenzymestotargetgenes,eitherincis(nearthesiteoflncRNAproduction)orintranstodistanttargetgenes.lncRNAscanbring

14、togethermultipleproteinstoformribonucleoproteincomplexeslncRNAscanbringtogethermultipleproteinstoformribonucleoproteincomplexes.ThelncRNA-RNPmayactonchromatinasillustratedtoaffecthistonemodifications.Inotherinstances,thelncRNAscaffoldisstructuralandstabilizesnuclearstructuresorsignalingcomplexesLong

15、intergenicnoncodingRNAs lie within the genomic intervals between two genes lncRNAs could be utilized for cancer diagnosis,prognosis,and serve as potential therapeutic targets involved in tumorigenesis and cancer metastasis and imprintingprocessesfunctionLongintronicnoncodingRNAscharacteristic Lie wi

16、thin the introns evolutionary conserved tissue and subcellular expression specificityfunctionLongintronicnoncodingRNAs aberrantly expressed in human cancers possible link with posttranscriptional gene silencingLongncRNAswithdualfunctionscharacteristic protein-coding Functionally regulatory RNA capac

17、ity deregulation in breast and ovarian tumors modulate gene expression through diverse mechanismsConclusionsandfutureperspectives Small ncRNAs are involved mainly in the post-transcriptional gene regulation using translational repression or RNAi pathway Long ncRNAs are much more involved in epigenet

18、ic regulation differential expression of ncRNAs is becoming recognized as a one of the hallmarks of cancer cell ncRNAs have the promising potential in targeted regulation of gene expression and,therefore,in cancer targeted therapyTheGENCODEv7catalogofhumanlongnoncodingRNAs:Analysisoftheirgenestructu

19、re,evolution,andexpressionTheselncRNAscanbeenfurtherreclassifiedintothefollowinglocusbiotypesbasedontheirlocationwithrespecttoprotein-codinggenes1.AntisenseRNAs：whichhavetranscriptsthatintersectanyexonofaprotein-codinglocusontheoppositestrand,orpublishedevidenceofantisenseregulationofacodinggene（323

20、3）l2.LincRNA：transcriptsthatareintergenicnoncodingRNAlociwithalength200bp（5094）3.overlappingtranscripts:containacodinggenewithinanintrononthesamestrand(unknow)4.intronictranscripts:residewithinintronsofacodinggene,butdonotintersectanyexons(378)Intergenic,then subclassified according to its transcrip

21、tion orientation with the closest protein-coding gene(same sense,convergent,or divergent).LncRNAsdonotshowevidenceofprotein-codingpotentialLncRNAsshowlowerandmoretissue-specificexpressionthanprotein-codinggeneslncRNAsshowlowerexpressioninalltissuescomparedwithmRNAsalthoughlncRNAsshowrelativelyhighex

22、pressionintestisLncRNAsalsoshowmoretissue-specificpatternscomparedwithprotein-codinggenesThemajority(65%)ofprotein-codinggenesweredetectedinallHBMtissuescomparedwith11%oflncRNAs(21%oflncRNAswerenotbedetectedinanytissue,and11%areonlydetectedinasingletissue)Almost40%(3934lncRNAgenes,5361transcripts)of

23、GENCODElncRNAsintersectprotein-codinggeneloci,anditispossiblethatsuchlncRNAssomehowcontributetotheregulationofthelatter(Fig.1B;Gingeras2007;Pasmantetal.2011).WethereforecomputedcorrelationsofexpressionbetweentheselncRNAgenesandtheirhostmRNAsCorrelationofexpressionbetweenoverlappinglncRNAsandmRNAsWef

24、oundthatlncRNAshavemorepositivecorrelationswithintersectingmRNAselementsthanexpectedbychanceThereismountingevidencethatmanylncRNAsarerecruitedtochromatinandepigeneticallyregulategeneexpressionThus,wewouldexpectthatlncRNAsshouldbepreferentiallylocalizedinthechromatinandnuclearRNAfractions,incontrastt

25、oprotein-codingmRNAsthataretraffickedtothecytoplasmfortranslationLncRNAsareenrichedinthenucleusInallcelllines,exceptforNHEK,weobservedarobustandhighlystatisticallysignificantenrichmentoflncRNAsinthenucleus,comparedwithprotein-codingmRNAs.Furthermore,thelncRNAsnuclear/cytoplasmicenrichmentisconsisten

26、tbetweencelltypesWealsotestedwhetherparticularclassesoflncRNAintergenic,intronic,antisensehaddistinctnuclearlocalizationpropensities,butwecouldfindnosignificantdifference,suggestingthatnuclearenrichmentisageneralpropertyoflongnon-protein-codingtranscriptsWealsotestedwhetherparticularclassesoflncRNAi

27、ntergenic,intronic,antisensehaddistinctnuclearlocalizationpropensities,butwecouldfindnosignificantdifference,suggestingthatnuclearenrichmentisageneralpropertyoflongnon-protein-codingtranscriptsWefurtherinvestigatedwhetherlncRNAsareenrichedinparticularcompartmentswithinthenucleus（chromatin）.LncRNAsar

28、esignificantlymoreenrichedinchromatinthanmRNAs:Themedianchromatin/nucleusexpressionratioforlncRNAsismorethantwicethatofmRNAs(0.55vs.0.26,respectively).ThislendsfurthersupporttotheideathatlncRNAsarespecificallyrecruitedtochromatin,wheretheyplayaregulatoryLongnoncodingRNAsarerarelytranslatedintwohuman

29、celllinesIntroductionslAparticularlyintriguingpropertyofmammalianlncRNAsistheirlackofevolutionaryconservation,relativetoprotein-codinggenes.lItisimportanceofusingempiricalmethodologiestodocumentwhetherlncRNAsareactuallynon-protein-coding.ResultslInwhole-cellRNA-seqdata,lncRNAexpressionlevelsareonave

30、rage24-foldlowerthanmRNAslAllpotentiallytranslatablelncRNAORFshadonlyasinglepeptidematch,indicatinglowproteinabundanceand/orfalse-positivepeptidematches.Resultsitremainspossiblethatextremelyshortorrapidlydegradedpolypeptidesexistthathavegoneundetected.LncRNAsare13-foldlesslikelytoproducedetectablepe

31、ptidesthansimilarmRNAs,indicatingthat92%ofGENCODEv7lncRNAsarenottranslatedinthesetwoENCODEcelllines.lOurgrouphasbroadresearchinterestsaboutnon-codingRNA,celldeath,cancerbiologyandbioinformatics.Usingdata-mining,statisticsapproachesandsystemsbiologytheories,etal,wewilltrytogeneratebiologicalhypothesesandmodels,andthenusesystemsbiologyapproachestovalidateandrefinemodelsandhypotheses.Happiness Enthusiasm Positive All the blessings we enjoy are the fruits of labor,toil,and self-denial,and study 我们得到的一切幸福都是劳动、辛苦、自我克制和学习的成果