title: A comprehensive analysis of 3' end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogeneous ribonucleoprotein C on cleavage and polyadenylation.
abstract: 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, six of which are 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 RBP 1 (ELAVL1) binding sites and include those of the 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.
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Gruber
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Gruber
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Georges
authors.initials: G
authors.lastname: Martin
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Souvik
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Belmadani
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Keller
authors.affiliation: Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Mihaela
authors.identifier: 0000-0002-8832-2041
authors.initials: M
authors.lastname: Zavolan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D003593:Cytoplasm / Q000235:genetics; D015870:Gene Expression; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000235:genetics*; D006801:Humans; D051379:Mice; D026723:Polyadenylation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D012333:RNA, Messenger; D016601:RNA-Binding Proteins