Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate
- Nova Fong1,3,
- Hyunmin Kim1,3,
- Yu Zhou2,
- Xiong Ji2,
- Jinsong Qiu2,
- Tassa Saldi1,
- Katrina Diener1,
- Ken Jones1,
- Xiang-Dong Fu2 and
- David L. Bentley1
- 1Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
- 2Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California at San Diego, San Diego, California 92093, USA
- Corresponding author: david.bentley{at}ucdenver.edu
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↵3 These authors contributed equally to this work.
Abstract
Alternative splicing modulates expression of most human genes. The kinetic model of cotranscriptional splicing suggests that slow elongation expands and that fast elongation compresses the “window of opportunity” for recognition of upstream splice sites, thereby increasing or decreasing inclusion of alternative exons. We tested the model using RNA polymerase II mutants that change average elongation rates genome-wide. Slow and fast elongation affected constitutive and alternative splicing, frequently altering exon inclusion and intron retention in ways not predicted by the model. Cassette exons included by slow and excluded by fast elongation (type I) have weaker splice sites, shorter flanking introns, and distinct sequence motifs relative to “slow-excluded” and “fast-included” exons (type II). Many rate-sensitive exons are misspliced in tumors. Unexpectedly, slow and fast elongation often both increased or both decreased inclusion of a particular exon or retained intron. These results suggest that an optimal rate of transcriptional elongation is required for normal cotranscriptional pre-mRNA splicing.
Keywords
- alternative splicing
- intron retention
- kinetic coupling
- transcription elongation rate
- cotranscriptional splicing
Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.252106.114.
- Received September 4, 2014.
- Accepted October 24, 2014.
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