的作用与调控机制

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1、CSLSRetreat2007MatanHofree&AssafWeiner1OutlineAbriefintroductiontomicroRNAProjectmotivationandgoalSelectingthedatasetsFeaturesanddataanalysisResultsandconclusions2WhataremicroRNAs?Non-codingRNAsthatregulategeneexpressionpost-transcriptionaly22~nucleotidelongEvolutionaryconservedLocatedinint

2、ergenicregionsorintronsOftenspecifictoaparticulartissueoradevelopmentalstageHumangenomesarepredictedtoencodeasmanyas1000uniquemiRs,thattogetherpossiblyregulateonethirdofallgenes11Bartelet.al.Cell(2005)3HowdomiRswork?Ambion,Inc.Explorationshttp://www.ambion.com/main/explorations/mirna.html4P

3、ossiblemechanismsofmiR-mediatedinhibitionofgeneexpressionTwoTypesofmechanismshavebeenobserved:Directeffectontranslation-Inhibitionofinitiation,elongationortermination.Indirecteffects–Affectsthenumberofavailabletranscriptsbydegradationorsequestration.5TimothyW.Nilsen(2007)MechanismsofmicroRN

4、A-mediatedgeneregulationinanimalcells,TrendsinGen.23,5,243-249.miR-targetinteractionprinciples6TargetsiteinmRNA3’UTRIncompletebasepairingG:Ubase-pairing7fullycomplementarybasesin5’ofmiRNA–‘Seed’He-L&Hannon-GJ(2004)miR-targetinteractionprinciples7EvolutionaryconservationoftargetsiteRepeating

5、bindingsiteinmanyoftheknowntargetgenesReinhart-BJet.al.(2000)Nature403:901Motivationforourwork“PerfectseedpairingisnotgenerallyareliablepredictorformiRNA-targetinteractions”DidianoD.&HobertO.(2006)Nat.Struct.Mol.8Experiment(modificationintarget)FunctionalNon-functionalwttargetsite(control)1

6、3putativetargets3’UTRwithseedmatchandphylogeneticconservationBindingsiteinrandom3’UTROriginaltargetsiteinothermiRregulated3’UTRMotivationforourworkConclusionsfromHobert’swork:ThepresenceofawellmatchedmiRtargetsitein3’UTRalone,isnotareliablepredictorforamiR-targetfunctionalinteraction.Propos

7、edmiR-targetinteractionspossiblyoccurinveryspecificcontexts.9Theseedisnotenough…10DiscerningthetruetargetsPossiblefactorscontributingtomiR-targetfunctionality:UniquemiR-targetduplexsecondarystructure3’UTRaccessibilityandtargetsiteaccessibilityRNA-binding