Discovery of global regulators of 3′ untranslated region processing in cancers with KAPAC

bioRxiv(2017)

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摘要
Background: The processing of 3′ untranslated regions (3′ UTRs) of messenger RNAs is coordinated in relation to the cellular state. Systematic changes in 3′ UTR length through corresponding changes in the use of alternative polyadenylation (poly(A)) sites have been reported in various systems, including human cancers, yet the key regulators remain largely unknown. Results: To uncover sequence elements that drive the use of poly(A) sites in specific conditions, we have developed PAQR, a method for quantifying poly(A) site use from RNA sequencing (RNA-seq) data and KAPAC, an approach that infers activities of oligomeric sequence motifs on poly(A) site choice. We demonstrate that these tools enable the discovery of sequence specificity and the binding site position-dependent activity of RNA-binding proteins (RBPs) on pre-mRNA cleavage and polyadenylation (CPA), from RNA-seq data obtained upon perturbing RBP expression. Furthermore, application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovered sequence motifs that can explain changes in CPA within specific cancer types. In particular, our analysis points to the polypyrimidine tract binding protein 1 as key regulator of poly(A) site choice in glioblastoma. Conclusions: The PAQR and KAPAC methods that we introduced here enable the identification of regulatory factors that shape 3′ UTR processing and the characterization of their binding position-dependent activity in physiological and pathological cell states, including human malignancies.
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关键词
Cleavage and polyadenylation,APA,CFIm,KAPAC,PAQR,HNRNPC,PTBP1,prostate adenocarcinoma,glioblastoma,colon adenocarcinoma
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