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Analysis of Cis-Regulatory Motifs in Cassette Exons by Incorporating Exon Skipping Rates

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Bioinformatics Research and Applications (ISBRA 2009)

Part of the book series: Lecture Notes in Computer Science ((LNBI,volume 5542))

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Abstract

Identification of cis-regulatory motifs has long been a hotspot in the study of alternative splicing. We propose a two-step approach: we first identify k-mer seed motifs by testing for enrichment and significant differences in exon skipping rate, then a local stochastic search is applied to refine the seed motifs. Our approach is especially suitable to discover short and degenerate motifs. We applied our method to a dataset of CNS-specific cassette exons in mouse and discovered 15 motifs. Two of these motifs are highly similar to validated motifs, Nova and hnRNP A1 binding sites. Four motifs show positional bias relative to the splice sites. Our study provides a dictionary of sequence motifs involved in the regulation of alternative splicing in CNS tissues, and a novel tool to detect such motifs.

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References

  1. Ladd, A.N., Cooper, T.A.: Finding Signals that Regulate Alternative Splicing in the Post-Genomic Era. Genome Biol. 3, reviews0008 (2002)

    Article  Google Scholar 

  2. Matlin, A.J., Clark, F., Smith, C.W.: Understanding Alternative Splicing: Towards a Cellular Code. Nat. Rev. Mol. Cell Biol. 6, 386–398 (2005)

    Article  CAS  PubMed  Google Scholar 

  3. Blencowe, B.J.: Alternative Splicing: New Insights from Global Analyses. Cell 126, 37–47 (2006)

    Article  CAS  PubMed  Google Scholar 

  4. Miriami, E., Margalit, H., Sperling, R.: Conserved Sequence Elements Associated with Exon Skipping. Nucleic Acids Res. 31, 1974–1983 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brudno, M., Gelfand, M.S., Spengler, S., Zorn, M., Dubchak, I., Conboy, J.G.: Computational Analysis of Candidate Intron Regulatory Elements for Tissue-Specific Alternative Pre-mRNA Splicing. Nucleic Acids Res. 29, 2338–2348 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fairbrother, W.G., Yeh, R.F., Sharp, P.A., Burge, C.B.: Predictive Identification of Exonic Splicing Enhancers in Human Genes. Science 297, 1007–1013 (2002)

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, X.H., Chasin, L.A.: Computational Definition of Sequence Motifs Governing Constitutive Exon Splicing. Genes Dev. 18, 1241–1250 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vingron, M., Brazma, A., Coulson, R., van Helden, J., Manke, T., Palin, K., Sand, O., Ukkonen, E.: Integrating Sequence, Evolution and Functional Genomics in Regulatory Genomics. Genome Biol. 10, 202 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bussemaker, H.J., Li, H., Siggia, E.D.: Regulatory Element Detection using Correlation with Expression. Nat. Genet. 27, 167–171 (2001)

    Article  CAS  PubMed  Google Scholar 

  10. Conlon, E.M., Liu, X.S., Lieb, J.D., Liu, J.S.: Integrating Regulatory Motif Discovery and Genome-Wide Expression Analysis. Proc. Natl. Acad. Sci. U.S.A. 100, 3339–3344 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith, A.D., Sumazin, P., Das, D., Zhang, M.Q.: Mining ChIP-Chip Data for Transcription Factor and Cofactor Binding Sites. Bioinformatics 21(suppl. 1), i403–i412 (2005)

    Article  Google Scholar 

  12. Fagnani, M., Barash, Y., Ip, J., Misquitta, C., Pan, Q., Saltzman, A., Shai, O., Lee, L., Rozenhek, A., Mohammad, N., Willaime-Morawek, S., Babak, T., Zhang, W., Hughes, T., van der Kooy, D., Frey, B., Blencowe, B.: Functional Coordination of Alternative Splicing in the Mammalian Central Nervous System. Genome Biol. 8, R108 (2007)

    Article  Google Scholar 

  13. Marchler-Bauer, A., Bryant, S.H.: CD-Search: Protein Domain Annotations on the Fly. Nucl. Acids Res. 32, W327–W331 (2004)

    Article  Google Scholar 

  14. Bailey, T.L., Elkan, C.: Fitting a Mixture Model by Expectation Maximization to Discover Motifs in Biopolymers. Proc. Int. Conf. Intell. Syst. Mol. Biol. 2, 28–36 (1994)

    CAS  PubMed  Google Scholar 

  15. Tsai, H.K., Huang, G.T., Chou, M.Y., Lu, H.H., Li, W.H.: Method for Identifying Transcription Factor Binding Sites in Yeast. Bioinformatics 22, 1675–1681 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. Pan, Q., Shai, O., Misquitta, C., Zhang, W., Saltzman, A.L., Mohammad, N., Babak, T., Siu, H., Hughes, T.R., Morris, Q.D., Frey, B.J., Blencowe, B.J.: Revealing Global Regulatory Features of Mammalian Alternative Splicing using a Quantitative Microarray Platform. Mol. Cell 16, 929–941 (2004)

    Article  CAS  PubMed  Google Scholar 

  17. Kent, W.J.: BLAT–the BLAST-Like Alignment Tool. Genome Res. 12, 656–664 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Smith, A.D., Sumazin, P., Zhang, M.Q.: Identifying Tissue-Selective Transcription Factor Binding Sites in Vertebrate Promoters. Proc. Natl. Acad. Sci. U.S.A 102, 1560–1565 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. McCullough, A.J., Berget, S.M.: G Triplets Located Throughout a Class of Small Vertebrate Introns Enforce Intron Borders and Regulate Splice Site Selection. Mol. Cell. Biol. 17, 4562–4571 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yeo, G., Holste, D., Kreiman, G., Burge, C.: Variation in Alternative Splicing Across Human Tissues. Genome Biol. 5, R74 (2004)

    Article  Google Scholar 

  21. Burd, C.G., Dreyfuss, G.: RNA Binding Specificity of hnRNP A1: Significance of hnRNP A1 High-Affinity Binding Sites in Pre-mRNA Splicing. EMBO J. 13, 1197–1204 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ule, J., Stefani, G., Mele, A., Ruggiu, M., Wang, X., Taneri, B., Gaasterland, T., Blencowe, B.J., Darnell, R.B.: An RNA Map Predicting Nova-Dependent Splicing Regulation. Nature 444, 580–586 (2006)

    Article  CAS  PubMed  Google Scholar 

  23. Zhao, X., Rush, M., Schwartz, S.: Identification of an hnRNP A1-Dependent Splicing Silencer in the Human Papillomavirus Type 16 L1 Coding Region that Prevents Premature Expression of the Late L1 Gene. J. Virol. 78, 10888–10905 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ule, J., Jensen, K.B., Ruggiu, M., Mele, A., Ule, A., Darnell, R.B.: CLIP Identifies Nova-Regulated RNA Networks in the Brain. Science 302, 1212–1215 (2003)

    Article  CAS  PubMed  Google Scholar 

  25. Sinha, S., Tompa, M.: YMF: A Program for Discovery of Novel Transcription Factor Binding Sites by Statistical Over representation. Nucleic Acids Res. 31, 3586–3588 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pavesi, G., Mereghetti, P., Mauri, G., Pesole, G.: Weeder Web: Discovery of Transcription Factor Binding Sites in a Set of Sequences from Co-Regulated Genes. Nucleic Acids Res. 203, W199–W203 (2004)

    Article  Google Scholar 

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© 2009 Springer-Verlag Berlin Heidelberg

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Zhao, S., Kim, J., Heber, S. (2009). Analysis of Cis-Regulatory Motifs in Cassette Exons by Incorporating Exon Skipping Rates. In: Măndoiu, I., Narasimhan, G., Zhang, Y. (eds) Bioinformatics Research and Applications. ISBRA 2009. Lecture Notes in Computer Science(), vol 5542. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-01551-9_27

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  • DOI: https://doi.org/10.1007/978-3-642-01551-9_27

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-01550-2

  • Online ISBN: 978-3-642-01551-9

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