Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain
Open accessAbstract
Fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43) are RNA-binding proteins pathogenetically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but it is not known if they regulate the same transcripts. We addressed this question using crosslinking and immunoprecipitation (iCLIP) in mouse brain, which showed that FUS binds along the whole length of the nascent RNA with limited sequence specificity to GGU and related motifs. A saw-tooth binding pattern in long genes demonstrated that FUS remains bound to pre-mRNAs until splicing is completed. Analysis of FUS(-/-) brain demonstrated a role for FUS in alternative splicing, with increased crosslinking of FUS in introns around the repressed exons. We did not observe a significant overlap in the RNA binding sites or the exons regulated by FUS and TDP-43. Nevertheless, we found that both proteins regulate genes that function in neuronal development.
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TDP43 and FUS regulate distinct groups of alternative exons and target different sets of mRNAs in the cytoplasm.
“TDP43 and FUS regulate distinct groups of alternative exons and target different sets of mRNAs in the cytoplasm178,181”
From The neurogenetics of alternative splicing (2016) · cites this paper as [178]
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References 52 · Cited by 278
- Authors
- Rogelj, B., Easton, L. E., Bogu, G. K., Stanton, L. W., Rot, G., Curk, T., Zupan, B., Sugimoto, Y., Modic, M., Haberman, N., Tollervey, J., Fujii, R., Takumi, T., Shaw, C. E., & Ule, J.
- Affiliations
- King's College London (GB)
- MRC Laboratory of Molecular Biology (GB)
- Genome Institute of Singapore (SG)
- University of Ljubljana (SI)
- Buck Institute for Research on Aging (US)
- Hiroshima University (JP)
- Corresponding author
- Shaw, Christopher E.
- Ule, Jernej
- ORCID
- Venue
- Scientific Reports
- Published
- 2012-08-28
- Volume
- 2
- Issue
- 1
- Pages
- 603-603
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC3429604
- OpenAlex
- W2007239552
- Cited by
- 278
- References
- 52
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 14 · 2023: 12 · 2022: 15 · 2021: 22 · 2020: 22 · 2019: 24 · 2018: 26 · 2017: 25 · 2016: 32 · 2015: 25 · 2014: 22 · 2013: 21 · 2012: 3
- FWCI
- 9.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust (089701, 089701/Z/09/Z)
- Ministry of Education, Culture, Sports, Science and Technology (CREST)
- Javna Agencija za Raziskovalno Dejavnost RS (J3-4026, J2-2197, L2-1112, P2-0209, Z7-3665)
- Medical Research Council (MC_G1000733)
- Japan Society for the Promotion of Science (22500335)
- Core Research for Evolutional Science and Technology
- FP7 Ideas: European Research Council (206726)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- FUS, TDP-43, alternative splicing, nascent RNA, RNA-binding proteins, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, pre-mRNA splicing, neuronal development, iCLIP
- MeSH terms
- Animals, Base Sequence, Brain, DNA-Binding Proteins, Exons, Gene Expression Regulation, Humans, Male, Neurons, Protein Binding, RNA Precursors, Alternative Splicing, Mice, Knockout, Gene Order, RNA-Binding Protein FUS, Mice, RNA Isoforms
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