title: Widespread intron retention in mammals functionally tunes transcriptomes.
abstract: Alternative splicing (AS) of precursor RNAs is responsible for greatly expanding the regulatory and functional capacity of eukaryotic genomes. Of the different classes of AS, intron retention (IR) is the least well understood. In plants and unicellular eukaryotes, IR is the most common form of AS, whereas in animals, it is thought to represent the least prevalent form. Using high-coverage poly(A)(+) RNA-seq data, we observe that IR is surprisingly frequent in mammals, affecting transcripts from as many as three-quarters of multiexonic genes. A highly correlated set of cis features comprising an "IR code" reliably discriminates retained from constitutively spliced introns. We show that IR acts widely to reduce the levels of transcripts that are less or not required for the physiology of the cell or tissue type in which they are detected. This "transcriptome tuning" function of IR acts through both nonsense-mediated mRNA decay and nuclear sequestration and turnover of IR transcripts. We further show that IR is linked to a cross-talk mechanism involving localized stalling of RNA polymerase II (Pol II) and reduced availability of spliceosomal components. Collectively, the results implicate a global checkpoint-type mechanism whereby reduced recruitment of splicing components coupled to Pol II pausing underlies widespread IR-mediated suppression of inappropriately expressed transcripts.
authors.affiliation: Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada;
authors.forename: Ulrich
authors.identifier: http://orcid.org/0000-0001-6653-0926
authors.initials: U
authors.lastname: Braunschweig
authors.affiliation: Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
authors.forename: Nuno L
authors.identifier: http://orcid.org/0000-0002-1215-0538
authors.initials: NL
authors.lastname: Barbosa-Morais
authors.affiliation: Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada;
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Ontario, M5S 1A8, Canada;
authors.forename: Emil N
authors.initials: EN
authors.lastname: Nachman
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4, Canada.
authors.forename: Babak
authors.initials: B
authors.lastname: Alipanahi
authors.affiliation: Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada;
authors.forename: Thomas
authors.initials: T
authors.lastname: Gonatopoulos-Pournatzis
authors.affiliation: Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Frey
authors.affiliation: Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada; b.blencowe@utoronto.ca mirimia@gmail.com.
authors.forename: Manuel
authors.initials: M
authors.lastname: Irimia
authors.affiliation: Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Ontario, M5S 1A8, Canada; b.blencowe@utoronto.ca mirimia@gmail.com.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
mesh_terms: D016475:3T3 Cells; D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019143:Evolution, Molecular; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics*; D020014:K562 Cells; D008322:Mammals / Q000145:classification / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D009928:Organ Specificity; D025341:Principal Component Analysis; D012319:RNA Polymerase II / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D059467:Transcriptome / Q000235:genetics*; D014714:Vertebrates / Q000145:classification / Q000235:genetics
chemical_list: D012322:RNA Precursors; D012319:RNA Polymerase II