Global and Local Architecture of the Mammalian microRNA–Transcription Factor Regulatory Network 英文参考文献.docVIP

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Global and Local Architecture of the Mammalian microRNA–Transcription Factor Regulatory Network 英文参考文献.doc

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Global and Local Architecture of the Mammalian microRNA–Transcription Factor Regulatory Network 英文参考文献

GlobalandLocalArchitecture oftheMammalianmicroRNA–Transcription FactorRegulatoryNetwork Reut Shalgi1,2,Daniel Lieber1,Moshe Oren2,Yitzhak Pilpel1* 1DepartmentofMolecularGenetics,WeizmannInstituteofScience,Rehovot,Israel,2DepartmentofMolecularCellBiology,WeizmannInstituteofScience,Rehovot,Israel microRNAs(miRs)aresmallRNAsthatregulategeneexpressionattheposttranscriptionallevel.Itisanticipatedthat,in combinationwithtranscriptionfactors(TFs),theyspanaregulatorynetworkthatcontrolsthousandsofmammalian genes.HerewesetouttouncoverlocalandglobalarchitecturalfeaturesofthemammalianmiRregulatorynetwork. UsingevolutionarilyconservedpotentialbindingsitesofmiRsinhumantargets,andconservedbindingsitesofTFsin promoters,weuncoveredtworegulationnetworks.ThefirstdepictscombinatorialinteractionsbetweenpairsofmiRs with many shared targets. The network reveals several levels of hierarchy, whereby a few miRs interact with many otherlowlyconnectedmiRpartners.Werevealedhundredsof‘‘targethubs’’genes,eachpotentiallysubjecttomassive regulationbydozensofmiRs.Interestingly,manyofthesetargethubgenesaretranscriptionregulatorsandtheyare oftenrelatedtovariousdevelopmentalprocesses.ThesecondnetworkconsistsofmiR–TFpairsthatcoregulatelarge sets of common targets. We discovered that the network consists of several recurring motifs. Most notably, in a significant fraction of the miR–TF coregulators the TF appears to regulate the miR, or to be regulated by the miR, forming a diversity of feed-forward loops. Together these findings provide new insights on the architecture of the combinedtranscriptional–posttranscriptionalregulatorynetwork. Citation:ShalgiR,LieberD,OrenM,PilpelY(2007)GlobalandlocalarchitectureofthemammalianmicroRNA–transcriptionfactorregulatorynetwork.PLoSComputBiol3(7): e131.doi:10.1371/journal.pcbi.0030131 accuracy [21]. Even more obvious is the lack of knowledge aboutthestructureofthemiRregulatorynetwork,andabout Introduction microRNAs(miRs)areshortRNAsthatposttranscription- ally regul