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Regulatory Circuit of Human MicroRNA Biogenesis 英文参考文献.doc

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Regulatory Circuit of Human MicroRNA Biogenesis 英文参考文献

RegulatoryCircuitofHumanMicroRNA Biogenesis JiLee1,2,Zhihua Li1,Rachel Brower-Sinning1,Bino John1,3* 1DepartmentofComputationalBiology,UniversityofPittsburghSchoolofMedicine,Pittsburgh,Pennsylvania,UnitedStatesofAmerica,2DepartmentofBioengineering, PennsylvaniaStateUniversity,UniversityPark,Pennsylvania,UnitedStatesofAmerica,3UniversityofPittsburghCancerInstitute,Pittsburgh,Pennsylvania,UnitedStatesof America miRNAs(microRNAs)areaclassofendogenoussmallRNAsthatarethoughttonegativelyregulateproteinproduction. Aberrant expression of many miRNAs is linked to cancer and other diseases. Little is known about the factors that regulatetheexpressionofmiRNAs.WehaveidentifiednumerousregulatoryelementsupstreamofmiRNAgenesthat are likely to be essential to the transcriptional and posttranscriptional regulation of miRNAs. Newly identified regulatorymotifsoccurfrequentlyandinmultiplecopiesupstreamofmiRNAs.ThemotifsarehighlyenrichedinGand C nucleotides, in comparison with the nucleotide composition of miRNA upstream sequences. Although the motifs were predicted using sequences that are upstream of miRNAs, we find that 99% of the top-predicted motifs preferentiallyoccurwithinthefirst500nucleotidesupstreamofthetranscriptionstartsitesofprotein-codinggenes; theobservedpreferenceinlocationunderscoresthevalidityandimportanceofthemotifsidentifiedinthisstudy.Our study also raises the possibility that a considerable number of well-characterized, disease-associated transcription factors(TFs)ofprotein-codinggenescontributetotheabnormalmiRNAexpressionindiseasessuchascancer.Further analysisofpredictedmiRNA–proteininteractionsleadustohypothesizethatTFsthatincludec-Myb,NF-Y,Sp-1,MTF- 1,andAP-2aaremaster-regulatorsofmiRNAexpression.Ourpredictionsareasolidstartingpointforthesystematic elucidationofthecausativebasisforaberrantexpressionpatternsofdisease-related(e.g.,cancer)miRNAs.Thus,we point out that focused studies of the TFs that regulate miRNAs will be paramount in developing cures for miRNA-