Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3'-UTR landscape across seven tumour types.

TitleDynamic analyses of alternative polyadenylation from RNA-seq reveal a 3'-UTR landscape across seven tumour types.
Publication TypeJournal Article
Year of Publication2014
AuthorsXia, Z, Donehower, LA, Cooper, TA, Neilson, JR, Wheeler, DA, Wagner, EJ, Li, W
JournalNat Commun
Volume5
Pagination5274
Date Published2014 Nov 20
ISSN2041-1723
Keywords3' Untranslated Regions, Gene Expression Regulation, Neoplastic, Humans, Neoplasms, Polyadenylation, RNA, Messenger, RNA-Binding Proteins, Sequence Analysis, RNA
Abstract

Alternative polyadenylation (APA) is a pervasive mechanism in the regulation of most human genes, and its implication in diseases including cancer is only beginning to be appreciated. Since conventional APA profiling has not been widely adopted, global cancer APA studies are very limited. Here we develop a novel bioinformatics algorithm (DaPars) for the de novo identification of dynamic APAs from standard RNA-seq. When applied to 358 TCGA Pan-Cancer tumour/normal pairs across seven tumour types, DaPars reveals 1,346 genes with recurrent and tumour-specific APAs. Most APA genes (91%) have shorter 3'-untranslated regions (3' UTRs) in tumours that can avoid microRNA-mediated repression, including glutaminase (GLS), a key metabolic enzyme for tumour proliferation. Interestingly, selected APA events add strong prognostic power beyond common clinical and molecular variables, suggesting their potential as novel prognostic biomarkers. Finally, our results implicate CstF64, an essential polyadenylation factor, as a master regulator of 3'-UTR shortening across multiple tumour types.

DOI10.1038/ncomms6274
Alternate JournalNat Commun
PubMed ID25409906
PubMed Central IDPMC4467577
Grant ListCA166274 / CA / NCI NIH HHS / United States
R01HG007538 / HG / NHGRI NIH HHS / United States
R01 AR045653 / AR / NIAMS NIH HHS / United States
R01 CA166274 / CA / NCI NIH HHS / United States
R01 AR060733 / AR / NIAMS NIH HHS / United States
CA167752 / CA / NCI NIH HHS / United States
R01 HG007538 / HG / NHGRI NIH HHS / United States
R01 HL045565 / HL / NHLBI NIH HHS / United States
R03 CA167752 / CA / NCI NIH HHS / United States