Advertisement

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

  • Sihui Zhao
  • Jihye Kim
  • Steffen Heber
Conference paper
Part of the Lecture Notes in Computer Science book series (LNCS, volume 5542)

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.

Keywords

alternative splicing motif discovery exon skipping rate 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ladd, A.N., Cooper, T.A.: Finding Signals that Regulate Alternative Splicing in the Post-Genomic Era. Genome Biol. 3, reviews0008 (2002)CrossRefGoogle Scholar
  2. 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)CrossRefPubMedGoogle Scholar
  3. 3.
    Blencowe, B.J.: Alternative Splicing: New Insights from Global Analyses. Cell 126, 37–47 (2006)CrossRefPubMedGoogle Scholar
  4. 4.
    Miriami, E., Margalit, H., Sperling, R.: Conserved Sequence Elements Associated with Exon Skipping. Nucleic Acids Res. 31, 1974–1983 (2003)CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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)CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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)CrossRefPubMedGoogle Scholar
  7. 7.
    Zhang, X.H., Chasin, L.A.: Computational Definition of Sequence Motifs Governing Constitutive Exon Splicing. Genes Dev. 18, 1241–1250 (2004)CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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)CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bussemaker, H.J., Li, H., Siggia, E.D.: Regulatory Element Detection using Correlation with Expression. Nat. Genet. 27, 167–171 (2001)CrossRefPubMedGoogle Scholar
  10. 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)CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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)CrossRefGoogle Scholar
  12. 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)CrossRefGoogle Scholar
  13. 13.
    Marchler-Bauer, A., Bryant, S.H.: CD-Search: Protein Domain Annotations on the Fly. Nucl. Acids Res. 32, W327–W331 (2004)CrossRefGoogle Scholar
  14. 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)PubMedGoogle Scholar
  15. 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)CrossRefPubMedGoogle Scholar
  16. 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)CrossRefPubMedGoogle Scholar
  17. 17.
    Kent, W.J.: BLAT–the BLAST-Like Alignment Tool. Genome Res. 12, 656–664 (2002)CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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)CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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)CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yeo, G., Holste, D., Kreiman, G., Burge, C.: Variation in Alternative Splicing Across Human Tissues. Genome Biol. 5, R74 (2004)CrossRefGoogle Scholar
  21. 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)PubMedPubMedCentralGoogle Scholar
  22. 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)CrossRefPubMedGoogle Scholar
  23. 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)CrossRefPubMedPubMedCentralGoogle Scholar
  24. 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)CrossRefPubMedGoogle Scholar
  25. 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)CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Sihui Zhao
    • 1
  • Jihye Kim
    • 1
  • Steffen Heber
    • 1
  1. 1.Bioinformatics Research CenterNorth Carolina State UniversityRaleighUSA

Personalised recommendations