An Integrated Regulatory Network Reveals Pervasive Cross-Regulation among Transcription and Splicing Factors 英文参考文献.docVIP

AnIntegratedRegulatoryNetworkRevealsPervasive Cross-RegulationamongTranscriptionandSplicing Factors IditKosti1,PredragRadivojac2,YaelMandel-Gutfreund1* 1Faculty of Biology, Technion – Israel Institute of Technology, Haifa, Israel, 2School of Informatics and Computing, Indiana University, Bloomington, Indiana, United StatesofAmerica Abstract Traditionally the gene expression pathway has been regarded as being comprised of independent steps, from RNA transcriptiontoproteintranslation.Todatethereisincreasingevidenceofcouplingbetweenthedifferentprocessesofthe pathway, specifically between transcription and splicing. To study the interplay between these processes we derived a transcription-splicing integrated network. The nodes of the network included experimentally verified human proteins belonging to three groups of regulators: transcription factors, splicing factors and kinases. The nodes were wired by instances of predicted transcriptional and alternative splicing regulation. Analysis of the network indicated a pervasive cross-regulation among the nodes; specifically, splicing factors are significantly more connected by alternative splicing regulatory edges relative to the two other subgroups, while transcription factors are more extensively controlled by transcriptionalregulation.Furthermore,wefoundthatsplicingfactorsarethemostregulatedofthethreeregulatorygroups andaresubjecttoextensivecombinatorialcontrolbyalternativesplicingandtranscriptionalregulation.Consistentwiththe networkresults,ourbioinformaticsanalysesshowedthatthesubgroupofkinaseshavethehighestdensity ofpredicted phosphorylationsites.Overall,oursystematicstudyrevealsthatanorganizingprincipleinthelogicofintegratednetworks favortheregulationofregulatoryproteinsbythespecificregulationtheyconduct.Basedontheseresults,weproposea newregulatoryparadigmpostulatingthatgeneexpressionregulationofthemasterregulatorsinthecellispredominantly achievedbycross-regulation. Citation:KostiI,RadivojacP,Mandel-Gutfreu