The ribosome-engaged landscape of alternative splicing
Open accessAbstract
High-throughput RNA sequencing (RNA-seq) has revealed an enormous complexity of alternative splicing (AS) across diverse cell and tissue types. However, it is currently unknown to what extent repertoires of splice-variant transcripts are translated into protein products. Here, we surveyed AS events engaged by the ribosome. Notably, at least 75% of human exon-skipping events detected in transcripts with medium-to-high abundance in RNA-seq data were also detected in ribosome profiling data. Furthermore, relatively small subsets of functionally related splice variants are engaged by ribosomes at levels that do not reflect their absolute abundance, thus indicating a role for AS in modulating translational output. This mode of regulation is associated with control of the mammalian cell cycle. Our results thus suggest that a major fraction of splice variants is translated and that specific cellular functions including cell-cycle control are subject to AS-dependent modulation of translation output.
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Computational approaches can predict isoform conservation and function, and Ribo-seq can survey alternative transcripts engaged to ribosomes, but these techniques stop short of assessing AS protein products empirically.
“Although computational approaches can predict isoform conservation and function (Li et al., 2017; Rodriguez et al., 2013) and Ribo-seq can survey alternative transcripts engaged to ribosomes (Weatheritt et al., 2016; van Heesch et al., 2019), these techniques stop short of assessing AS protein products empirically.”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Weatheritt et al., 2016
Only a minority of expressed transcripts have the potential to be translated, whereas the rest may be removed by nonsense-mediated decay (NMD) or co-translational proteolysis.
“Only a minority of expressed transcripts have the potential to be translated (Hao et al., 2015), whereas the rest may be removed by nonsense-mediated decay (NMD) or co-translational proteolysis (Weatheritt et al., 2016).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Weatheritt et al., 2016
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- Authors
- Weatheritt, R. J., Sterne-Weiler, T., & Blencowe, B. J.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- University of Toronto (CA)
- Corresponding author
- Weatheritt, Robert J
- Blencowe, Benjamin J
- Venue
- Nature Structural & Molecular Biology
- Published
- 2016-11-07
- Volume
- 23
- Issue
- 12
- Pages
- 1117-1123
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC5295628
- OpenAlex
- W2554777987
- Cited by
- 162
- References
- 56
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 14 · 2023: 15 · 2022: 22 · 2021: 13 · 2020: 18 · 2019: 17 · 2018: 14 · 2017: 19 · 2016: 1
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/I004718/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- alternative splicing, exon skipping, ribosome profiling, translational regulation, cell cycle regulation, splice variants, mRNA levels
- MeSH terms
- Animals, Cell Cycle, Humans, Introns, Ribosomes, RNA, Messenger, RNA, Ribosomal, Alternative Splicing, Sequence Analysis, RNA, 5' Untranslated Regions, Genomics, Mice, High-Throughput Nucleotide Sequencing
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