The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons
Open accessAbstract
Previous studies have identified UGCAUG as an intron splicing enhancer that is frequently located adjacent to tissue-specific alternative exons in the human genome. Here, we show that UGCAUG is phylogenetically and spatially conserved in introns that flank brain-enriched alternative exons from fish to man. Analysis of sequence from the mouse, rat, dog, chicken and pufferfish genomes revealed a strongly statistically significant association of UGCAUG with the proximal intron region downstream of brain-enriched alternative exons. The number, position and sequence context of intronic UGCAUG elements were highly conserved among mammals and in chicken, but more divergent in fish. Control datasets, including constitutive exons and non-tissue-specific alternative exons, exhibited a much lower incidence of closely linked UGCAUG elements. We propose that the high sequence specificity of the UGCAUG element, and its unique association with tissue-specific alternative exons, mark it as a critical component of splicing switch mechanism(s) designed to activate a limited repertoire of splicing events in cell type-specific patterns. We further speculate that highly conserved UGCAUG-binding protein(s) related to the recently described Fox-1 splicing factor play a critical role in mediating this specificity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Rbfox proteins bind the (U)GCAUG element, which is frequently conserved across vertebrates.
“Rbfox proteins are known as tissue-specific splicing factors which bind to the (U)GCAUG element frequently conserved across vertebrate species (Jin et al., 2003; Minovitsky et al., 2005; Ponthier et al., 2006; Underwood et al., 2005).”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Minovitsky et al., 2005
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
ESEfinder: a web resource to identify exonic splicing enhancers
Cartegni, L. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg616 · Cited by 1,593 · see citing works
CLIP Identifies Nova-Regulated RNA Networks in the Brain
Ule, J., Jensen, K. B., Ruggiu, M., Mele, A., Ule, A., & Darnell, R. B. (2003) · Science · doi:10.1126/science.1090095 · Cited by 1,120 · see citing works
Predictive Identification of Exonic Splicing Enhancers in Human Genes
Fairbrother, W. G., Yeh, R., Sharp, P. A., & Burge, C. B. (2002) · Science · doi:10.1126/science.1073774 · Cited by 1,020 · see citing works
Systematic Identification and Analysis of Exonic Splicing Silencers
Wang, Z., Rolish, M. E., Yeo, G. W.-M., Tung, V., Mawson, M., & Burge, C. B. (2004) · Cell · doi:10.1016/j.cell.2004.11.010 · Cited by 678 · see citing works
Identification of functional exonic splicing enhancer motifs recognized by individual SR proteinsPreprint
Liu, H., Zhang, M. Q., & Krainer, A. R. (1998) · Genes & Development · doi:10.1101/gad.12.13.1998 · Cited by 513 · see citing works
Ladd, A. N., Charlet‐Berguerand, N., & Cooper, T. A. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.4.1285-1296.2001 · Cited by 449 · see citing works
Nova-1 Regulates Neuron-Specific Alternative Splicing and Is Essential for Neuronal Viability
Jensen, K. B., Dredge, B. K., Stefani, G., Zhong, R., Buckanovich, R. J., Okano, H. J., Yang, Y. Y. L., & Darnell, R. B. (2000) · Neuron · doi:10.1016/s0896-6273(00)80900-9 · Cited by 426 · see citing works
Computational definition of sequence motifs governing constitutive exon splicingPreprint
Zhang, X. H.-F., & Chasin, L. A. (2004) · Genes & Development · doi:10.1101/gad.1195304 · Cited by 416 · see citing works
Zhu, J., Mayeda, A., & Krainer, A. R. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00409-9 · Cited by 396 · see citing works
Tacke, R., & Manley, J. L. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07360.x · Cited by 373 · see citing works
Jin, Y., Suzuki, H., Maegawa, S., Endo, H., Sugano, S., Hashimoto, K., Yasuda, K., & Inoue, K. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg089 · Cited by 311 · see citing works
How prevalent is functional alternative splicing in the human genome?
Sorek, R., Shamir, R., & Ast, G. (2003) · Trends in Genetics · doi:10.1016/j.tig.2003.12.004 · Cited by 305 · see citing works
RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons
Fairbrother, W. G., Yeo, G. W.-M., Yeh, R., Goldstein, P., Mawson, M., Sharp, P. A., & Burge, C. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh393 · Cited by 288 · see citing works
Intronic Sequences Flanking Alternatively Spliced Exons Are Conserved Between Human and MousePreprint
Sorek, R., & Ast, G. (2003) · Genome Research · doi:10.1101/gr.1208803 · Cited by 276 · see citing works
Exonic Splicing Enhancer Motif Recognized by Human SC35 under Splicing Conditions
Liu, H., Chew, S. L., Cartegni, L., Zhang, M. Q., & Krainer, A. R. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.3.1063-1071.2000 · Cited by 244 · see citing works
Identification of a New Class of Exonic Splicing Enhancers by In Vivo Selection
Coulter, L. R., Landree, M. A., & Cooper, T. A. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.4.2143 · Cited by 238 · see citing works
Schaal, T. D., & Maniatis, T. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.3.1705 · Cited by 235 · see citing works
The splicing regulator TIA‐1 interacts with U1‐C to promote U1 snRNP recruitment to 5′ splice sites
Förch, P., Puig, Ó., Martínez, C., Séraphin, B., & Valcárcel, J. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf668 · Cited by 229 · see citing works
The splicing factors 9G8 and SRp20 transactivate splicing through different and specific enhancers
Cavaloc, Y., Bourgeois, C. F., Kister, L., & Stévenin, J. (1999) · RNA · doi:10.1017/s1355838299981967 · Cited by 228 · see citing works
Variation in sequence and organization of splicing regulatory elements in vertebrate genes
Yeo, G. W.-M., Hoon, S. S., Venkatesh, B., & Burge, C. B. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404901101 · Cited by 226 · see citing works
McCullough, A. J., & Berget, S. M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.8.4562 · Cited by 223 · see citing works
A novel protein with RNA-binding motifs interacts with ataxin-2
Shibata, H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.9.1303 · Cited by 221 · see citing works
Blanchette, M., & Chabot, B. (1999) · The EMBO Journal · doi:10.1093/emboj/18.7.1939 · Cited by 205 · see citing works
Dynamic Antagonism between ETR-3 and PTB Regulates Cell Type-Specific Alternative Splicing
Charlet‐Berguerand, N., Singh, G., Cooper, T. A., & Logan, P. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00479-3 · Cited by 190 · see citing works
Minimal Conditions for Exonization of Intronic Sequences
Sorek, R., Lev-Maor, G., Reznik, M., Dagan, T., Belinky, F., Graur, D., & Ast, G. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00181-9 · Cited by 169 · see citing works
Regulation of alternative pre-mRNA splicing by a novel repeated hexanucleotide element.Preprint
Huh, G. S., & Hynes, R. O. (1994) · Genes & Development · doi:10.1101/gad.8.13.1561 · Cited by 155 · see citing works
Low conservation of alternative splicing patterns in the human and mouse genomes
Nurtdinov, R. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg137 · Cited by 147 · see citing works
Modafferi, E. F., & Black, D. L. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.11.6537 · Cited by 132 · see citing works
Zhang, X. H.-F. (2003) · Genome Research · doi:10.1101/gr.1679003 · Cited by 132 · see citing works
Brudno, M. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.11.2338 · Cited by 119 · see citing works
Sirand‐Pugnet, P., Durosay, P., Brody, E. N., & Marie, J. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.17.3501 · Cited by 114 · 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
Burgess, H. A., & Reiner, O. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111981200 · Cited by 105 · see citing works
Gromak, N., Matlin, A. J., Cooper, T. A., & Smith, C. W. J. (2003) · RNA · doi:10.1261/rna.2191903 · Cited by 103 · see citing works
MAGI-1: A Widely Expressed, Alternatively Spliced Tight Junction Protein
Laura, R. P., Ross, S., Koeppen, H., & Lasky, L. A. (2002) · Experimental Cell Research · doi:10.1006/excr.2002.5475 · Cited by 98 · see citing works
Roles for SR Proteins and hnRNP A1 in the Regulation of c -src Exon N1
Rooke, N., Markovtsov, V. V., Çağavi, E., & Black, D. L. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.6.1874-1884.2003 · Cited by 92 · see citing works
An Intronic Splicing Enhancer Binds U1 snRNPs To Enhance Splicing and Select 5′ Splice Sites
McCullough, A. J., & Berget, S. M. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.24.9225-9235.2000 · Cited by 91 · see citing works
Neuronal Cell Expression of Inserted Isoforms of Vertebrate Nonmuscle Myosin Heavy Chain II-B
Itoh, K., & Adelstein, R. S. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.24.14533 · Cited by 76 · see citing works
Kawamoto, S. (1996) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)86956-9 · Cited by 74 · see citing works
Structure and Organization of the Human Ankyrin-1 Gene
Gallagher, P. G., Tse, W. T., Scarpa, A. L., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19220 · Cited by 72 · see citing works
Specific SR protein-dependent splicing substrates identified through genomic SELEX
Kim, S. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg286 · Cited by 69 · see citing works
Control of alternative pre-mRNA splicing by distributed pentameric repeats
Hedjran, F., Yeakley, J. M., Huh, G. S., Hynes, R. O., & Rosenfeld, M. G. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.23.12343 · Cited by 55 · see citing works
Rahman, L., Bliskovski, V., Reinhold, W. C., & Zajac‐Kaye, M. (2002) · Genomics · doi:10.1006/geno.2002.6826 · Cited by 42 · see citing works
Parra, M., Gee, S. L., Chan, N., Ryaboy, D. V., Dubchak, I. L., Mohandas, N., Gascard, P. D., & Conboy, J. G. (2004) · Genomics · doi:10.1016/j.ygeno.2004.06.004 · Cited by 35 · see citing works
Nussinov, R. (1989) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.1989.10506526 · Cited by 33 · see citing works
An Intronic Downstream Enhancer Promotes 3′ Splice Site Usage of a Neural Cell-specific Exon
Guo, N.-H., & Kawamoto, S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005597200 · Cited by 30 · see citing works
Characterization of a new brain‐specific isoform of the EWS oncoprotein
Melot, T., Dauphinot, L., Sévenet, N., Radvanyi, F., & Delattre, O. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02251.x · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges
Lovci, M. T., Ghanem, D., Marr, H., Arnold, J., Gee, S., Parra, M., Liang, T. Y., Stark, T. J., Gehman, L. T., Hoon, S., et al. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2699 · Cited by 385 · see citing works
Neuronal regulation of alternative pre-mRNA splicing
Li, Q., Lee, J.-A., & Black, D. L. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2237 · Cited by 376 · see citing works
Weyn-Vanhentenryck, S. M., Mele, A., Yan, Q., Sun, S., Farny, N., Zhang, Z., Xue, C., Herre, M., Silver, P. A., Zhang, M. Q., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.005 · Cited by 333 · see citing works
Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2
Zhang, C., Zhang, Z., Castle, J., Sun, S., Johnson, J., Krainer, A. R., & Zhang, M. Q. (2008) · Genes & Development · doi:10.1101/gad.1703108 · Cited by 300 · see citing works
Underwood, J. G., Boutz, P. L., Dougherty, J. D., Stoilov, P., & Black, D. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.22.10005-10016.2005 · Cited by 272 · see citing works
Fox-1 family of RNA-binding proteins
Kuroyanagi, H. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0120-5 · Cited by 187 · see citing works
Functional coordination of alternative splicing in the mammalian central nervous system
Fagnani, M., Barash, Y., Ip, J. Y., Misquitta, C., Pan, Q., Saltzman, A. L., Shai, O., Lee, L., Rozenhek, A., Mohammad, N., et al. (2007) · Genome Biology · doi:10.1186/gb-2007-8-6-r108 · Cited by 120 · see citing works
Calarco, J. A., Zhen, M., & Blencowe, B. J. (2011) · RNA · doi:10.1261/rna.2603911 · Cited by 72 · see citing works
Ponthier, J. L., Schluepen, C., Chen, W., Lersch, R. A., Gee, S. L., Hou, V. C., Lo, A. J., Short, S. A., Chasis, J. A., Winkelmann, J. C., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511556200
- Authors
- Minovitsky, S.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Minovitsky, S.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-01-19
- Volume
- 33
- Issue
- 2
- Pages
- 714-724
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC548355
- OpenAlex
- W2019518393
- Cited by
- 103
- References
- 47
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 5
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- other-oa
- Locations
- Nucleic Acids Research (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy (DE-AC03-?, AC03-76SF00098, DEAC03-76SF00098)
- National Institutes of Health (DE-AC03- 76SF00098)
- National Heart, Lung, and Blood Institute (R01HL045182, HL45182, R56HL045182)
- Biological and Environmental Research
- 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, phylogenetic conservation, splicing regulation, comparative genomics
- MeSH terms
- Animals, Base Sequence, Brain, Chickens, Dogs, Exons, Humans, Introns, Phylogeny, Tissue Distribution, Conserved Sequence, Alternative Splicing, Tetraodontiformes, Regulatory Sequences, Ribonucleic Acid, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review