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Quantitative and predictive model of transcriptional control of the Drosophila melanogaster even skipped gene

Abstract

Here we present a quantitative and predictive model of the transcriptional readout of the proximal 1.7 kb of the control region of the Drosophila melanogaster gene even skipped (eve). The model is based on the positions and sequence of individual binding sites on the DNA and quantitative, time-resolved expression data at cellular resolution. These data demonstrated new expression features, first reported here. The model correctly predicts the expression patterns of mutations in trans, as well as point mutations, insertions and deletions in cis. It also shows that the nonclassical expression of stripe 7 driven by this fragment is activated by the protein Caudal (Cad), and repressed by the proteins Tailless (Tll) and Giant (Gt).

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Figure 1: Dynamic quantitative expression of a lacZ reporter construct.
Figure 2: Summary of model output.
Figure 3: Schematic view of 1.7 kb of eve 5′ regulatory sequences.
Figure 4: Regulatory analysis of stripe 7 expression. Analysis of the 17-site model (a,d,g,j), the 22-site model (b,e,h,k) and the 34-site model (c,f,i,l) at T5. (a–c) Model output in comparison with data.
Figure 5: Model predictions.

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References

  1. Banerji, J., Rusconi, S. & Schaffner, W. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308 (1981).

    Article  CAS  Google Scholar 

  2. Yuh, C.-H., Bolouri, H. & Davidson, E.H. Cis-regulatory logic in the endo16 gene: switching from a specification to a differentiation mode of control. Development 128, 617–629 (2001).

    CAS  PubMed  Google Scholar 

  3. Berman, B.P. et al. Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proc. Natl. Acad. Sci. USA 99, 757–762 (2002).

    Article  CAS  Google Scholar 

  4. Berman, B.P. et al. Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura. Genome Biol. 5, R61 (2004).

    Article  Google Scholar 

  5. Clyde, D.E. et al. A self-organizing system of repressor gradients establishes segmental complexity in Drosophila. Nature 426, 849–853 (2003).

    Article  CAS  Google Scholar 

  6. Rajewsky, N., Vergassola, M., Gaul, U. & Siggia, E.D. Computational detection of genomic cis-regulatory modules applied to body patterning in the early Drosophila embryo. BMC Bioinformatics 3, 30 (2002).

    Article  Google Scholar 

  7. Schroeder, M.D. et al. Transcriptional control in the segmentation gene network of Drosophila. PLoS Biol. 2, e271 (2004).

    Article  Google Scholar 

  8. Gray, S., Szymanski, P. & Levine, M. Short-range repression permits multiple enhancers to function autonomously within a complex promoter. Genes Dev. 8, 1829–1838 (1994).

    Article  CAS  Google Scholar 

  9. Goto, T., MacDonald, P. & Maniatis, T. Early and late periodic patterns of even-skipped expression are controlled by distinct regulatory elements that respond to different spatial cues. Cell 57, 413–422 (1989).

    Article  CAS  Google Scholar 

  10. Harding, K., Hoey, T., Warrior, R. & Levine, M. Autoregulatory and gap gene response elements of the even-skipped promoter of Drosophila. EMBO J. 8, 1205–1212 (1989).

    Article  CAS  Google Scholar 

  11. Small, S., Blair, A. & Levine, M. Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J. 11, 4047–4057 (1992).

    Article  CAS  Google Scholar 

  12. Small, S., Arnosti, D.N. & Levine, M. Spacing ensures autonomous expression of different stripe enhancers in the even-skipped promoter. Development 119, 767–772 (1993).

    CAS  Google Scholar 

  13. Small, S., Blair, A. & Levine, M. Regulation of two pair-rule stripes by a single enhancer in the Drosophila embryo. Dev. Biol. 175, 314–324 (1996).

    Article  CAS  Google Scholar 

  14. Ludwig, M. et al. Functional evolution of a cis-regulatory module. PLoS Biol. 3, e93 (2005).

    Article  Google Scholar 

  15. Reinitz, J., Hou, S. & Sharp, D.H. Transcriptional control in Drosophila. ComPlexUs 1, 54–64 (2003).

    Article  CAS  Google Scholar 

  16. Stanojevic, D., Small, S. & Levine, M. Regulation of a segmentation stripe by overlapping activators and repressors in the Drosophila embryo. Science 254, 1385–1387 (1991).

    Article  CAS  Google Scholar 

  17. Stormo, G.D. DNA binding sites: representation and discovery. Bioinformatics 16, 16–23 (2000).

    Article  CAS  Google Scholar 

  18. Stanojevic, D., Hoey, T. & Levine, M. Sequence-specific DNA-binding activities of the gap proteins encoded by hunchback and Krüppel in Drosophila. Nature 341, 331–335 (1989).

    Article  CAS  Google Scholar 

  19. Small, S., Kraut, R., Hoey, T., Warrior, R. & Levine, M. Transcriptional regulation of a pair-rule stripe in Drosophila. Genes Dev. 5, 827–839 (1991).

    Article  CAS  Google Scholar 

  20. Arnosti, D.N., Barolo, S., Levine, M. & Small, S. The eve stripe 2 enhancer employs multiple modes of transcriptional synergy. Development 122, 205–214 (1996).

    CAS  Google Scholar 

  21. Pankratz, M.J., Hoch, M., Seifert, E. & Jäckle, H. Krüppel requirement for knirps enhancement reflects overlapping gap gene activities in the Drosophila embryo. Nature 341, 337–340 (1989).

    Article  CAS  Google Scholar 

  22. Rothe, M., Wimmer, E.A., Pankratz, M.J., González-Gaitán, M. & Jäckle, H. Identical transacting factor requirement for knirps and knirps-related gene expression in the anterior but not in the posterior region of the Drosophila embryo. Mech. Dev. 46, 169–181 (1994).

    Article  CAS  Google Scholar 

  23. Steingrimsson, E., Pignoni, F., Liaw, G.J. & Lengyel, J.A. Dual role of the Drosophila pattern gene tailless in embryonic termini. Science 254, 418–421 (1991).

    Article  CAS  Google Scholar 

  24. Fujioka, M., Jaynes, J.B. & Goto, T. Early even-skipped stripes act as morphogenetic gradients at the single cell level to establish engrailed expression. Development 121, 4371–4382 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hughes, S.C. & Krause, H.M. Single and double FISH protocols for Drosophila. in Confocal Microscopy Methods and Protocols: Methods in Molecular Biology Vol. 122 (ed. Paddock, S.W.) 93–101 (Humana Press, Totowa, New Jersey, 1998).

    Chapter  Google Scholar 

  26. Wu, X., Vasisht, V., Kosman, D., Reinitz, J. & Small, S. Thoracic patterning by the Drosophila gap gene hunchback. Dev. Biol. 237, 79–92 (2001).

    Article  CAS  Google Scholar 

  27. Nagaso, H., Murata, T., Day, N. & Yokoyama, K.K. Simultaneous detection of RNA and protein by in situ hybridization and immunological staining. J. Histochem. Cytochem. 49, 1177–1182 (2001).

    Article  CAS  Google Scholar 

  28. Kosman, D., Small, S. & Reinitz, J. Rapid preparation of a panel of polyclonal antibodies to Drosophila segmentation proteins. Dev. Genes Evol. 208, 290–294 (1998).

    Article  CAS  Google Scholar 

  29. Janssens, H. et al. A high-throughput method for quantifying gene expression data from early Drosophila embryos. Dev. Genes Evol. 215, 374–381 (2005).

    Article  CAS  Google Scholar 

  30. Jaeger, J. et al. Dynamical analysis of regulatory interactions in the gap gene system of Drosophila melanogaster. Genetics 167, 1721–1737 (2004).

    Article  CAS  Google Scholar 

  31. Myasnikova, E., Samsonova, M., Kosman, D. & Reinitz, J. Removal of background signal from in situ data on the expression of segmentation genes in Drosophila. Dev. Genes Evol. 215, 320–326 (2005).

    Article  Google Scholar 

  32. Myasnikova, E., Samsonova, A., Kozlov, K., Samsonova, M. & Reinitz, J. Registration of the expression patterns of Drosophila segmentation genes by two independent methods. Bioinformatics 17, 3–12 (2001).

    Article  CAS  Google Scholar 

  33. Elsner, J. & Tsonis, A. Singular Spectrum Analysis: a New Tool in Time Series Analysis (Plenum, New York, 1996).

    Book  Google Scholar 

  34. Hertz, G.Z. & Stormo, G.D. Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics 15, 563–577 (1999).

    Article  CAS  Google Scholar 

  35. Capovilla, M., Eldon, E.D. & Pirrotta, V. The giant gene of Drosophila encodes a b-ZIP DNA-binding protein that regulates the expression of other segmentation gap genes. Development 114, 99–112 (1992).

    CAS  PubMed  Google Scholar 

  36. Lam, J. & Delosme, J.-M. An efficient simulated annealing schedule: derivation. Technical Report 8816 (Yale Electrical Engineering Department, New Haven, Connecticut, 1988).

    Google Scholar 

  37. Lam, J. & Delosme, J.-M. An efficient simulated annealing schedule: Implementation and evaluation. Technical Report 8817 (Yale Electrical Engineering Department, New Haven, Connecticut, 1988).

    Google Scholar 

  38. Reinitz, J. & Sharp, D.H. Mechanism of eve stripe formation. Mech. Dev. 49, 133–158 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P. Gergen for comments on the manuscript. E.M., H.J., J.J., A.K. and J.R. were supported by US National Institutes of Health grant 2 ROI RR07801. D.S., H.J. and S.H. were supported in part by contract W-7405-ENG-36 from the US Department of Energy. H.J. received partial support from the State University of New York.

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Correspondence to John Reinitz.

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Supplementary information

Supplementary Fig. 1

Matrix representing the quenching function q(d) for the 34-site model. (PDF 30 kb)

Supplementary Fig. 2

Expression data of transcription factors and lacZ mRNA. (PDF 55 kb)

Supplementary Fig. 3

Model output. (PDF 102 kb)

Supplementary Fig. 4

Parameter distribution. (PDF 41 kb)

Supplementary Fig. 5

Graphical analysis of expression in the posterior region of the embryo. (PDF 47 kb)

Supplementary Fig. 6

Regulatory analysis of expression near 64% AP position. (PDF 69 kb)

Supplementary Fig. 7

Regulatory analysis of stripe 2 formation. (PDF 55 kb)

Supplementary Table 1

Binding sites used in modeling. (PDF 87 kb)

Supplementary Table 2

Root mean square (rms) scores of models. (PDF 42 kb)

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Janssens, H., Hou, S., Jaeger, J. et al. Quantitative and predictive model of transcriptional control of the Drosophila melanogaster even skipped gene. Nat Genet 38, 1159–1165 (2006). https://doi.org/10.1038/ng1886

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