PT - JOURNAL ARTICLE AU - Andreas J. Gruber AU - Ralf Schmidt AU - Andreas R. Gruber AU - Georges Martin AU - Souvik Ghosh AU - Manuel Belmadani AU - Walter Keller AU - Mihaela Zavolan TI - A comprehensive analysis of 3’ end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogenous ribonucleoprotein C on cleavage and polyadenylation AID - 10.1101/033001 DP - 2015 Jan 01 TA - bioRxiv PG - 033001 4099 - http://biorxiv.org/content/early/2015/11/26/033001.short 4100 - http://biorxiv.org/content/early/2015/11/26/033001.full AB - Alternative polyadenylation (APA) is a general mechanism of transcript diversification in mammals, which has been recently linked to proliferative states and cancer. Different 3’ untranslated region (3’ UTR) isoforms interact with different RNA binding proteins (RBPs), which modify the stability, translation, and subcellular localization of the corresponding transcripts. Although the heterogeneity of pre-mRNA 3’ end processing has been established with high-throughput approaches, the mechanisms that underlie systematic changes in 3’ UTR lengths remain to be characterized. Through a uniform analysis of a large number of 3’ end sequencing data sets we have uncovered 18 signals, 6 of which novel, whose positioning with respect to pre-mRNA cleavage sites indicates a role in pre-mRNA 3’ end processing in both mouse and human. With 3’ end sequencing we have demonstrated that the heterogeneous ribonucleoprotein C (HNRNPC), which binds the poly(U) motif whose frequency also peaks in the vicinity of polyadenylation (poly(A)) sites, has a genome-wide effect on poly(A) site usage. HNRNPC-regulated 3’ UTRs are enriched in ELAV-like RNA binding protein 1 (ELAVL1) binding sites and include those of the CD47 molecule (CD47) gene, which participate in the recently discovered mechanism of 3’ UTR-dependent protein localization (UDPL). Our study thus establishes an up-to-date, high-confidence catalog of 3’ end processing sites and poly(A) signals and it uncovers an important role of HNRNPC in regulating 3’ end processing. It further suggests that U-rich elements mediate interactions with multiple RBPs that regulate different stages in a transcript’s life cycle.