Widespread intron retention in mammals functionally tunes transcriptomes

  1. Benjamin J. Blencowe1,3
  1. 1Donnelly Centre, University of Toronto, Ontario, M5S 3E1, Canada;
  2. 2Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal;
  3. 3Department of Molecular Genetics, University of Toronto, Ontario, M5S 1A8, Canada;
  4. 4Department of Electrical and Computer Engineering, University of Toronto, Ontario, M5S 2E4, Canada
  1. Corresponding authors: b.blencowe{at}utoronto.ca, mirimia{at}gmail.com
  • Present addresses: 5Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom;

  • 6 EMBL/CRG Research Unit in Systems Biology, Centre for Genomic Regulation (CRG), Barcelona, 08003, Spain.

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.

Footnotes

  • Received May 6, 2014.
  • Accepted July 23, 2014.

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