title: 3'UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells.
abstract: Most mammalian genes often feature alternative polyadenylation (APA) sites and hence diverse 3'UTR lengths. Proliferating cells were reported to favor APA sites that result in shorter 3'UTRs. One consequence of such shortening is escape of mRNAs from targeting by microRNAs (miRNAs) whose binding sites are eliminated. Such a mechanism might provide proliferation-related genes with an expression gain during normal or cancerous proliferation. Notably, miRNA sites tend to be more active when located near both ends of the 3'UTR compared to those located more centrally. Accordingly, miRNA sites located near the center of the full 3'UTR might become more active upon 3'UTR shortening. To address this conjecture we performed 3' sequencing to determine the 3' ends of all human UTRs in several cell lines. Remarkably, we found that conserved miRNA binding sites are preferentially enriched immediately upstream to APA sites, and this enrichment is more prominent in pro-differentiation/anti-proliferative genes. Binding sites of the miR17-92 cluster, upregulated in rapidly proliferating cells, are particularly enriched just upstream to APA sites, presumably conferring stronger inhibitory activity upon shortening. Thus 3'UTR shortening appears not only to enable escape from inhibition of growth promoting genes but also to potentiate repression of anti-proliferative genes.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.|Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yonit
authors.initials: Y
authors.lastname: Hoffman
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Debora Rosa
authors.initials: DR
authors.lastname: Bublik
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Alejandro P
authors.initials: AP
authors.lastname: Ugalde
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tammy
authors.initials: T
authors.lastname: Biniashvili
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Pilpel
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D026723:Polyadenylation; D062085:RNA, Long Noncoding
chemical_list: D020413:3' Untranslated Regions; C568997:MIR17HG, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding