A Slow RNA Polymerase II Affects Alternative Splicing In Vivo
Open accessAbstract
Changes in promoter structure and occupation have been shown to modify the splicing pattern of several genes, evidencing a coupling between transcription and alternative splicing. It has been proposed that the promoter effect involves modulation of RNA pol II elongation rates. The C4 point mutation of the Drosophila pol II largest subunit confers on the enzyme a lower elongation rate. Here we show that expression of a human equivalent to Drosophila's C4 pol II in human cultured cells affects alternative splicing of the fibronectin EDI exon and adenovirus E1a pre-mRNA. Most importantly, resplicing of the Hox gene Ultrabithorax is stimulated in Drosophila embryos mutant for C4, which demonstrates the transcriptional control of alternative splicing on an endogenous gene. These results provide a direct proof for the elongation control of alternative splicing in vivo.
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Slow and fast transcription either increased or decreased inclusion of alternative exons depending on the genes analyzed.
“Indeed, the use of gel‐based methods in yeast, human, and mouse cells (de la Mata et al, 2003; Howe et al, 2003; Schor et al, 2009; Ip et al, 2011; Dujardin et al, 2014) or of RNA sequencing‐based methods in human cells (Fong et al, 2014) showed that slow and fast transcription either increased or decreased inclusion of alternative exons depending on the genes analyzed.”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as de la Mata et al, 2003
At least two different mutations in human RNA Pol II are known to slow down transcription.
“At least two different mutations in human RNA Pol II are known to slow down transcription.”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as de la Mata et al, 2003
Cites
Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., & Tuschl, T. (2001) · Nature · doi:10.1038/35078107 · Cited by 9,456 · see citing works
An extensive network of coupling among gene expression machines
Maniatis, T., & Reed, R. (2002) · Nature · doi:10.1038/416499a · Cited by 1,148 · see citing works
Integrating mRNA Processing with Transcription
Proudfoot, N. J., Furger, A., & Dye, M. J. (2002) · Cell · doi:10.1016/s0092-8674(02)00617-7 · Cited by 1,084 · see citing works
The C-terminal domain of RNA polymerase II couples mRNA processing to transcription
McCracken, S. A., Fong, N., Yankulov, K., Ballantyne, S. M., Pan, G., Greenblatt, J., Patterson, S. D., Wickens, M., & Bentley, D. L. (1997) · Nature · doi:10.1038/385357a0 · Cited by 925 · see citing works
Self-citationAlternative splicing: multiple control mechanisms and involvement in human disease
Cáceres, J. F., & Kornblihtt, A. R. (2002) · Trends in Genetics · doi:10.1016/s0168-9525(01)02626-9 · Cited by 654 · see citing works
Self-citationRegulation of Alternative Splicing in Vivo by Overexpression of Antagonistic Splicing Factors
Cáceres, J. F., Stamm, S., Helfman, D. M., & Krainer, A. R. (1994) · Science · doi:10.1126/science.8085156 · Cited by 619 · see citing works
Coordinate Regulation of Transcription and Splicing by Steroid Receptor Coregulators
Auboeuf, D., Hönig, A., Berget, S. M., & O’Malley, B. W. (2002) · Science · doi:10.1126/science.1073734 · Cited by 357 · see citing works
Functional association between promoter structure and transcript alternative splicing
Cramer, P., Pesce, C. G., Baralle, F. E., & Kornblihtt, A. R. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.21.11456 · Cited by 344 · see citing works
Self-citationRegulated tissue-specific expression of antagonistic pre-mRNA splicing factors.
Hanamura, A., Cáceres, J. F., Mayeda, A., Franza, B. R., & Krainer, A. R. (1998) · PubMed Central · Cited by 329 · see citing works
On the importance of being co-transcriptional
Neugebauer, K. M. (2002) · Journal of Cell Science · doi:10.1242/jcs.00073 · Cited by 316 · see citing works
Coupling of Transcription with Alternative Splicing
Cramer, P., Cáceres, J. F., Cazalla, D., Kadener, S., Muro, A. F., Baralle, F. E., & Kornblihtt, A. R. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80372-x · Cited by 310 · see citing works
Self-citationThe mRNA assembly line: transcription and processing machines in the same factory
Bentley, D. L. (2002) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(02)00333-2 · Cited by 261 · see citing works
Self-citationIn vivo degradation of RNA polymerase II largest subunit triggered by alpha-amanitin
Nguyen, V. T. (1996) · Nucleic Acids Research · doi:10.1093/nar/24.15.2924 · Cited by 257 · see citing works
Transcriptional Activators Differ in Their Abilities to Control Alternative Splicing
Nogués, G., Kadener, S., Cramer, P., Bentley, D. L., & Kornblihtt, A. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208418200 · Cited by 189 · see citing works
Self-citationHOWE, K. J., KANE, C. M., & ARES, M. (2003) · RNA · doi:10.1261/rna.5390803 · Cited by 169 · see citing works
RNA polymerase II C-terminal domain required for enhancer-driven transcription
Gerber, H. P., Hagmann, M., Seipel, K., Georgiev, O., West, M. A. L., Litingtung, Y., Schaffner, W., & Corden, J. L. (1995) · Nature · doi:10.1038/374660a0 · Cited by 157 · see citing works
Kadener, S., Cramer, P., Nogués, G., et al. (2001) · The EMBO Journal · doi:10.1093/emboj/20.20.5759 · Cited by 150 · see citing works
Self-citationCaputi, M., Casari, G., Guenzi, S., et al. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.6.1018 · Cited by 144 · see citing works
Muro, A. F., Caputi, M., Pariyarath, R., et al. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.4.2657 · Cited by 134 · see citing works
Regulation of alternative splicing by a transcriptional enhancer through RNA pol II elongation
Kadener, S., Fededa, J. P., Rosbash, M., & Kornblihtt, A. R. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122246099 · Cited by 126 · see citing works
Self-citationHatton, A. R., Subramaniam, V., & Lopez, A. J. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80293-2 · Cited by 123 · see citing works
Alternative Splicing of the Fibronectin EIIIB Exon Depends on Specific TGCATG Repeats
Lim, L. P., & Sharp, P. A. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.7.3900 · Cited by 107 · see citing works
Genetic and biochemical characterization of mutants at an RNA polymerase II locus in D. melanogaster
Greenleaf, A. L. (1980) · Cell · doi:10.1016/0092-8674(80)90441-9 · Cited by 101 · see citing works
A mutation in the largest subunit of RNA polymerase II alters RNA chain elongation in vitro.
Coulter, D. E., & Greenleaf, A. L. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)38855-5 · Cited by 84 · see citing works
Promoter Architecture Modulates CFTR Exon 9 Skipping
Pagani, F., Stuani, C., Zuccato, E., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209676200 · Cited by 82 · see citing works
Drosophila RNA Polymerase II Mutants That Affect Transcription Elongation
Chen, Y., Chafin, D. R., Price, D. H., & Greenleaf, A. L. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.11.5993 · Cited by 44 · see citing works
Adami, G. R., & Babiss, L. E. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb04910.x · Cited by 37 · see citing works
Simard, M. J., & Chabot, B. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.19.7353-7362.2000 · Cited by 21 · see citing works
Antagonistic interactions between alleles of the RpII215 locus in Drosophila melanogaster.
Mortin, M. A., Kim, W. J., & Huang, J. (1988) · Genetics · doi:10.1093/genetics/119.4.863 · Cited by 19 · see citing works
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Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., Evantal, N., Memczak, S., Rajewsky, N., & Kadener, S. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.019 · Cited by 3,083 · see citing works
Self-citationMechanisms and Regulation of Alternative Pre-mRNA Splicing
Lee, Y., & Rio, D. C. (2015) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060614-034316 · Cited by 1,291 · see citing works
Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches
Chen, M., & Manley, J. L. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2777 · Cited by 1,284 · see citing works
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Shukla, S., Kavak, E., Gregory, M., Imashimizu, M., Shutinoski, B., Kashlev, M., Oberdoerffer, P., Sandberg, R., & Oberdoerffer, S. (2011) · Nature · doi:10.1038/nature10442 · Cited by 973 · see citing works
Getting up to speed with transcription elongation by RNA polymerase II
Jonkers, I., & Lis, J. T. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3953 · Cited by 876 · see citing works
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Bentley, D. L. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3662 · Cited by 828 · see citing works
Self-citationMechanisms and Consequences of Alternative Polyadenylation
Di Giammartino, D. C., Nishida, K., & Manley, J. L. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.017 · Cited by 737 · see citing works
The Biogenesis of Nascent Circular RNAs
Zhang, Y., Xue, W., Li, X., Zhang, J., Chen, S., Zhang, J.-L., Yang, L., & Chen, L.-L. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.058 · Cited by 643 · see citing works
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Schwartz, S., Meshorer, E., & Ast, G. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1659 · Cited by 638 · see citing works
Jonkers, I., Kwak, H., & Lis, J. T. (2014) · eLife · doi:10.7554/elife.02407 · Cited by 581 · see citing works
Maunakea, A. K., Chepelev, I., Cui, K., & Zhao, K. (2013) · Cell Research · doi:10.1038/cr.2013.110 · Cited by 552 · see citing works
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Singh, J., & Padgett, R. A. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1666 · Cited by 487 · see citing works
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Braberg, H., Jin, H., Moehle, E. A., Chan, Y. A., Wang, S., Shales, M., Benschop, J. J., Morris, J. H., Qiu, C., Hu, F., et al. (2013) · Cell · doi:10.1016/j.cell.2013.07.033 · Cited by 143 · see citing works
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- Authors
- de la Mata, M., Alonso, C. R., Kadener, S., Fededa, J. P., Blaustein, M., Pelisch, F., Cramer, P., Bentley, D., & Kornblihtt, A. R.
- Affiliations
- University of Cambridge (GB)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Corresponding author
- Kornblihtt, Alberto R
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 12
- Issue
- 2
- Pages
- 525-532
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1973697733
- Cited by
- 683
- References
- 29
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 17 · 2023: 20 · 2022: 25 · 2021: 40 · 2020: 29 · 2019: 40 · 2018: 20 · 2017: 29 · 2016: 29 · 2015: 39 · 2014: 44 · 2013: 46 · 2012: 50
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Repositorio Digital Institucional de la Universidad de Buenos Aires (Universidad de Buenos Aires) (publishedVersion, other-oa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of General Medical Sciences (R01GM058613, GM58613)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- RNA polymerase II, alternative splicing, transcription-splicing coupling, Drosophila, Ultrabithorax, Hox genes
- MeSH terms
- Adenoviridae, Amanitins, Animals, Dose-Response Relationship, Drug, Drosophila melanogaster, Exons, Fibronectins, Humans, Models, Biological, Models, Genetic, Plasmids, Promoter Regions, Genetic, Ribonucleases, RNA, RNA Polymerase II, RNA, Messenger, Time Factors, Transcription Factors, Transfection, Point Mutation, Alternative Splicing, Adenovirus E1A Proteins, Homeodomain Proteins, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Drosophila Proteins, Cell Line, Tumor
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