TAILIEUCHUNG - Discovery of physiological and cancerrelated regulators of 3′ UTR processing with KAPAC

3′ Untranslated regions (3' UTRs) length is regulated in relation to cellular state. To uncover key regulators of poly(A) site use in specific conditions, we have developed PAQR, a method for quantifying poly(A) site use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on poly(A) site choice. | Gruber et al. Genome Biology 2018 19 44 https s13059-018-1415-3 METHOD Open Access Discovery of physiological and cancer- related regulators of 3 UTR processing with KAPAC Andreas J. Gruber Ralf Schmidt Souvik Ghosh Georges Martin Andreas R. Gruber Erik van Nimwegen and Mihaela Zavolan Abstract 3 Untranslated regions 3 UTRs length is regulated in relation to cellular state. To uncover key regulators of poly A site use in specific conditions we have developed PAQR a method for quantifying poly A site use from RNA sequencing data and KAPAC an approach that infers activities of oligomeric sequence motifs on poly A site choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovers motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular our analysis points to polypyrimidine tract binding protein 1 as a regulator of poly A site choice in glioblastoma. Keywords Cleavage and polyadenylation APA CFIm KAPAC PAQR HNRNPC PTBP1 Prostate adenocarcinoma Glioblastoma Colon adenocarcinoma Background signal consisting of the CPSF1 CPSF4 FIP1L1 and The 3 ends of most eukaryotic mRNAs are generated WDR33 proteins has been identified 6 7 . through endonucleolytic cleavage and polyadenylation Most genes have multiple poly A sites PAS which CPA 1 3 . These steps are carried out in mammalian are differentially processed across cell types 8 likely cells by a 3 end processing complex composed of the due to cell type-specific interactions with RNA-binding cleavage and polyadenylation specificity factor which in- proteins RBPs . The length of 3 UTRs is most strongly cludes the proteins CPSF1 also known as CPSF160 dependent on the mammalian cleavage factor I CFIm CPSF2 CPSF100 CPSF3 CPSF73 CPSF4 CPSF30 which promotes the use of distal poly A sites 5 9 12 . FIP1L1 and WDR33 the mammalian cleavage factor I Reduced expression of CFIm 25 has been linked to 3 CFIm a tetramer of two small NUDT21

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