Pervasive isoform‐specific translational regulation via alternative transcription start sites in mammals
Open accessAbstract
Transcription initiated at alternative sites can produce mRNA isoforms with different 5ʹUTRs, which are potentially subjected to differential translational regulation. However, the prevalence of such isoform‐specific translational control across mammalian genomes is currently unknown. By combining polysome profiling with high‐throughput mRNA 5ʹ end sequencing, we directly measured the translational status of mRNA isoforms with distinct start sites. Among 9,951 genes expressed in mouse fibroblasts, we identified 4,153 showed significant initiation at multiple sites, of which 745 genes exhibited significant isoform‐divergent translation. Systematic analyses of the isoform‐specific translation revealed that isoforms with longer 5ʹUTRs tended to translate less efficiently. Further investigation of cis‐ elements within 5ʹUTRs not only provided novel insights into the regulation by known sequence features, but also led to the discovery of novel regulatory sequence motifs. Quantitative models integrating all these features explained over half of the variance in the observed isoform‐divergent translation. Overall, our study demonstrated the extensive translational regulation by usage of alternative transcription start sites and offered comprehensive understanding of translational regulation by diverse sequence features embedded in 5ʹUTRs.
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Polysome profiling has been used extensively to measure translation of native RNA isoforms, but isolating the role of 5′ UTR regulation has been difficult due to differences in the size and sequence of the concomitant coding sequences and 3′ UTRs.
“Polysome profiling has been used extensively to measure translation of native RNA isoforms14,15 but isolating the role of 5′ UTR regulation has been difficult due to differences in the size and sequence of the concomitant coding sequences and 3′ UTRs.”
From Human 5′ UTR design and variant effect prediction from a massively parallel translation assay (2019) · cites this paper as [15]
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Human 5′ UTR design and variant effect prediction from a massively parallel translation assay
Sample, P. J., Wang, B., Reid, D. W., Presnyak, V., McFadyen, I. J., Morris, D. R., & Seelig, G. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0164-5 · Cited by 442 · see citing works
Sikorski, P. J., Warminski, M., Kubacka, D., Ratajczak, T., Nowis, D., Kowalska, J., & Jemielity, J. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa032 · Cited by 142 · see citing works
- Authors
- Wang, X., Hou, J., Quedenau, C., & Chen, W.
- Affiliations
- Max Delbrück Center (DE)
- Corresponding author
- Chen, Wei
- Venue
- Molecular Systems Biology
- Published
- 2016-07-01
- Volume
- 12
- Issue
- 7
- Pages
- 875-875
- ISSN
- 1744-4292 (ISSN-L)
- PMC
- PMC4965872
- OpenAlex
- W2489659673
- Cited by
- 90
- References
- 6
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 12 · 2023: 2 · 2022: 11 · 2021: 5 · 2020: 13 · 2019: 15 · 2018: 8 · 2017: 8 · 2016: 3
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Systems Biology (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Federal Ministry for Education and Research
- Senate of Berlin, Berlin, Germany (BIMSB 0315362A, 0315362C)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- alternative transcription start sites, translational regulation, 5' untranslated region, mRNA isoforms, polysome profiling, 5' end sequencing, cis-regulatory elements, mouse fibroblasts
- MeSH terms
- Animals, Gene Expression Regulation, Mammals, Polyribosomes, RNA, Messenger, Protein Biosynthesis, Sequence Analysis, RNA, 5' Untranslated Regions, Transcription Initiation Site, NIH 3T3 Cells, Mice
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