Abstract
Using a physically principled method of scoring genomic sequences for the potential to be bound by transcription factors, we have developed an algorithm for assessing the conservation of predicted binding occupancy that does not rely on sequence alignment of promoters. The method, which we call ortholog-weighting, assesses the degree to which the predicted binding occupancy of a transcription factor in a reference gene is also predicted in the promoters of orthologous genes. The analysis was performed separately for over 100 different transcription factors in S. cerevisiae. Statistical significance was evaluated by simulation using permuted versions of the position weight matrices. Ortholog-weighting produced about twice as many significantly high scoring genes as were obtained from the S. cerevisiae genome alone. Gene Ontology analysis found a similar two-fold enrichment of genes. Both analyses suggest that ortholog-weighting improves the prediction of true regulatory targets. Interestingly, the method has only a marginal effect on the prediction of binding by chromatin immunoprecipitation (ChIP) assays. We suggest several possibilities for reconciling this result with the improved enrichment that we observe for functionally related promoters and for promoters that are under positive selection.
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References
Granek, J.A., Clarke, N.D.: Explicit equilibrium modeling of transcription-factor binding and gene regulation. Genome Biol. 6, R87 (2005)
Liu, X., Clarke, N.D.: Rationalization of gene regulation by a eukaryotic transcription factor: calculation of regulatory region occupancy from predicted binding affinities. J. Mol. Biol. 323, 1–8 (2002)
Liu, X., Lee, C.K., Granek, J.A., Clarke, N.D., Lieb, J.D.: Whole-genome comparison of Leu3 binding in vitro and in vivo reveals the importance of nucleosome occupancy in target site selection. Genome Res. 16, 1517–1528 (2006)
Cliften, P., Sudarsanam, P., Desikan, A., Fulton, L., Fulton, B., Majors, J., Waterston, R., Cohen, B.A., Johnston, M.: Finding functional features in Saccharomyces genomes by phylogenetic footprinting. Science 301, 71–76 (2003)
Wasserman, W.W., Sandelin, A.: Applied bioinformatics for the identification of regulatory elements. Nature reviews 5, 276–287 (2004)
Moses, A.M., Pollard, D.A., Nix, D.A., Iyer, V.N., Li, X.Y., Biggin, M.D., Eisen, M.B.: Large-scale turnover of functional transcription factor binding sites in Drosophila. PLoS computational biology 2, e130 (2006)
Borneman, A.R., Gianoulis, T.A., Zhang, Z.D., Yu, H., Rozowsky, J., Seringhaus, M.R., Wang, L.Y., Gerstein, M., Snyder, M.: Divergence of transcription factor binding sites across related yeast species. Science 317, 815–819 (2007)
Odom, D.T., Dowell, R.D., Jacobsen, E.S., Gordon, W., Danford, T.W., MacIsaac, K.D., Rolfe, P.A., Conboy, C.M., Gifford, D.K., Fraenkel, E.: Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature genetics 39, 730–732 (2007)
Aerts, S., van Helden, J., Sand, O., Hassan, B.A.: Fine-Tuning Enhancer Models to Predict Transcriptional Targets across Multiple Genomes. PLoS ONEÂ 2, e1115 (2007)
Pritsker, M., Liu, Y.C., Beer, M.A., Tavazoie, S.: Whole-genome discovery of transcription factor binding sites by network-level conservation. Genome Res. 14, 99–108 (2004)
Tanay, A.: Extensive low-affinity transcriptional interactions in the yeast genome. Genome Res. 16, 962–972 (2006)
Saccharomyces Genome Database
Harbison, C.T., Gordon, D.B., Lee, T.I., Rinaldi, N.J., Macisaac, K.D., Danford, T.W., Hannett, N.M., Tagne, J.B., Reynolds, D.B., Yoo, J., Jennings, E.G., Zeitlinger, J., Pokholok, D.K., Kellis, M., Rolfe, P.A., Takusagawa, K.T., Lander, E.S., Gifford, D.K., Fraenkel, E., Young, R.A.: Transcriptional regulatory code of a eukaryotic genome. Nature 431, 99–104 (2004)
Phillips, M.J., Delsuc, F., Penny, D.: Genome-scale phylogeny and the detection of systematic biases. Molecular biology and evolution 21, 1455–1458 (2004)
Rokas, A., Williams, B.L., King, N., Carroll, S.B.: Genome-scale approaches to resolving incongruence in molecular phylogenies. Nature 425, 798–804 (2003)
Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D., Butler, H., Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T., Harris, M.A., Hill, D.P., Issel-Tarver, L., Kasarskis, A., Lewis, S., Matese, J.C., Richardson, J.E., Ringwald, M., Rubin, G.M., Sherlock, G.: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature Genetics 25, 25–29 (2000)
Vardhanabhuti, S., Wang, J., Hannenhalli, S.: Position and distance specificity are important determinants of cis-regulatory motifs in addition to evolutionary conservation. Nucleic acids research 35, 3203–3213 (2007)
Moses, A.M., Chiang, D.Y., Pollard, D.A., Iyer, V.N., Eisen, M.B.: MONKEY: identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model. Genome Biol. 5, R98 (2004)
Hu, Z., Hu, B., Collins, J.F.: Prediction of synergistic transcription factors by function conservation. Genome Biol. 8, R257 (2007)
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Liu, X., Clarke, N.D. (2009). Transcription Factor Binding Probabilities in Orthologous Promoters: An Alignment-Free Approach to the Inference of Functional Regulatory Targets. In: Ciccarelli, F.D., Miklós, I. (eds) Comparative Genomics. RECOMB-CG 2009. Lecture Notes in Computer Science(), vol 5817. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-04744-2_19
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DOI: https://doi.org/10.1007/978-3-642-04744-2_19
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