Transcriptional regulatory code of a eukaryotic genome

Abstract

DNA-binding transcriptional regulators interpret the genome's regulatory code by binding to specific sequences to induce or repress gene expression1. Comparative genomics has recently been used to identify potential cis-regulatory sequences within the yeast genome on the basis of phylogenetic conservation2,3,4,5,6, but this information alone does not reveal if or when transcriptional regulators occupy these binding sites. We have constructed an initial map of yeast's transcriptional regulatory code by identifying the sequence elements that are bound by regulators under various conditions and that are conserved among Saccharomyces species. The organization of regulatory elements in promoters and the environment-dependent use of these elements by regulators are discussed. We find that environment-specific use of regulatory elements predicts mechanistic models for the function of a large population of yeast's transcriptional regulators.

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Figure 1: Discovering binding-site specificities for yeast transcriptional regulators.
Figure 2: Drafting the yeast transcriptional regulatory map.
Figure 3: Yeast promoter architectures: single regulator architecture, promoter regions that contain one or more copies of the binding site sequence for a single regulator; repetitive motif architecture, promoter regions that contain multiple copies of a binding site sequence of a regulator; multiple regulator architecture, promoter regions that contain one or more copies of the binding site sequences for more than one regulator; co-occurring regulator architecture, promoters that contain binding site sequences for recurrent pairs of regulators.
Figure 4: Environment-specific use of the transcriptional regulatory code.

References

  1. 1

    Jacob, F. & Monod, J. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356 (1961)

    CAS  Article  Google Scholar 

  2. 2

    Kellis, M., Patterson, N., Endrizzi, M., Birren, B. & Lander, E. S. Sequencing and comparison of yeast species to identify genes and regulatory elements. Nature 423, 241–254 (2003)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Cliften, P. et al. Finding functional features in Saccharomyces genomes by phylogenetic footprinting. Science 301, 71–76 (2003)

    ADS  CAS  Article  Google Scholar 

  4. 4

    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)

    CAS  Article  Google Scholar 

  5. 5

    Wang, T. & Stormo, G. D. Combining phylogenetic data with co-regulated genes to identify regulatory motifs. Bioinformatics 19, 2369–2380 (2003)

    CAS  Article  Google Scholar 

  6. 6

    Blanchette, M. & Tompa, M. FootPrinter: A program designed for phylogenetic footprinting. Nucleic Acids Res. 31, 3840–3842 (2003)

    CAS  Article  Google Scholar 

  7. 7

    Iyer, V. R. et al. Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409, 533–538 (2001)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306–2309 (2000)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Lee, T. I. et al. Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298, 799–804 (2002)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Lieb, J. D., Liu, X., Botstein, D. & Brown, P. O. Promoter-specific binding of Rap1 revealed by genome–wide maps of protein-DNA association. Nature Genet. 28, 327–334 (2001)

    CAS  Article  Google Scholar 

  11. 11

    Roth, F. P., Hughes, J. D., Estep, P. W. & Church, G. M. Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation. Nature Biotechnol. 16, 939–945 (1998)

    CAS  Article  Google Scholar 

  12. 12

    Liu, X. S., Brutlag, D. L. & Liu, J. S. An algorithm for finding protein-DNA binding sites with applications to chromatin-immunoprecipitation microarray experiments. Nature Biotechnol. 20, 835–839 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Bailey, T. L. & Elkan, C. Proc. Int. Conf. Intell. Syst. Mol. Biol. Vol. 3 21–29 (AAAI Press, Menlo Park, California, 1995)

    Google Scholar 

  14. 14

    Knuppel, R., Dietze, P., Lehnberg, W., Frech, K. & Wingender, E. TRANSFAC retrieval program: a network model database of eukaryotic transcription regulating sequences and proteins. J. Comput. Biol. 1, 191–198 (1994)

    CAS  Article  Google Scholar 

  15. 15

    Cunningham, T. S. & Cooper, T. G. The Saccharomyces cerevisiae DAL80 repressor protein binds to multiple copies of GATAA-containing sequences (URSGATA). J. Bacteriol. 175, 5851–5861 (1993)

    CAS  Article  Google Scholar 

  16. 16

    Donahue, T. F., Daves, R. S., Lucchini, G. & Fink, G. R. A short nucleotide sequence required for regulation of HIS4 by the general control system of yeast. Cell 32, 89–98 (1983)

    CAS  Article  Google Scholar 

  17. 17

    Kirkpatrick, C. R. & Schimmel, P. Detection of leucine-independent DNA site occupancy of the yeast Leu3p transcriptional activator in vivo. Mol. Cell. Biol. 15, 4021–4030 (1995)

    CAS  Article  Google Scholar 

  18. 18

    Axelrod, J. D., Majors, J. & Brandriss, M. C. Proline-independent binding of PUT3 transcriptional activator protein detected by footprinting in vivo. Mol. Cell. Biol. 11, 564–567 (1991)

    CAS  Article  Google Scholar 

  19. 19

    Ma, J. & Ptashne, M. The carboxy-terminal 30 amino acids of GAL4 are recognized by GAL80. Cell 50, 137–142 (1987)

    CAS  Article  Google Scholar 

  20. 20

    Beck, T. & Hall, M. N. The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature 402, 689–692 (1999)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Chi, Y. et al. Negative regulation of Gcn4 and Msn2 transcription factors by Srb10 cyclin-dependent kinase. Genes Dev. 15, 1078–1092 (2001)

    CAS  Article  Google Scholar 

  22. 22

    Albrecht, G., Mosch, H. U., Hoffmann, B., Reusser, U. & Braus, G. H. Monitoring the Gcn4 protein-mediated response in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 273, 12696–12702 (1998)

    CAS  Article  Google Scholar 

  23. 23

    Kornitzer, D., Raboy, B., Kulka, R. G. & Fink, G. R. Regulated degradation of the transcription factor Gcn4. EMBO J. 13, 6021–6030 (1994)

    CAS  Article  Google Scholar 

  24. 24

    Zeitlinger, J. et al. Program-specific distribution of a transcription factor dependent on partner transcription factor and MAPK signaling. Cell 113, 395–404 (2003)

    CAS  Article  Google Scholar 

  25. 25

    Baur, M., Esch, R. K. & Errede, B. Cooperative binding interactions required for function of the Ty1 sterile responsive element. Mol. Cell. Biol. 17, 4330–4337 (1997)

    CAS  Article  Google Scholar 

  26. 26

    Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Matys, V. et al. TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 31, 374–378 (2003)

    CAS  Article  Google Scholar 

  28. 28

    Hodges, P. E., McKee, A. H., Davis, B. P., Payne, W. E. & Garrels, J. I. The Yeast Proteome Database (YPD): a model for the organization and presentation of genome-wide functional data. Nucleic Acids Res. 27, 69–73 (1999)

    CAS  Article  Google Scholar 

  29. 29

    Zhu, J. & Zhang, M. Q. SCPD: a promoter database of the yeast Saccharomyces cerevisiae. Bioinformatics 15, 607–611 (1999)

    CAS  Article  Google Scholar 

  30. 30

    Schneider, T. D. & Stephens, R. M. Sequence logos: a new way to display consensus sequences. Nucleic Acids Res. 18, 6097–6100 (1990)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank T. Ideker and S. McCuine for help in selecting regulators to study in environmental conditions; E. Herbolsheimer, G. Bell, R. Latek and F. Lewitter for computational assistance; and E. McReynolds for technical assistance. E.F. is a Whitehead Fellow and was funded in part by Pfizer. D.B.G. was supported by a NIH/NIGMS NRSA award. This work was supported by an NIH grant.

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Correspondence to Ernest Fraenkel or Richard A. Young.

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Some authors have filed a patent application covering aspects of this work and are pursuing commercialization.

Supplementary information

Supplementary Figures 1-5

These figures show distributions of regulator binding, an overview of our motif-discover process, an example of in vitro regulator binding, the effect of environmental conditions on genomic binding, and a change in the quality of Gcn4 binding sites in different environmental conditions. (PDF 2001 kb)

Supplementary Tables 1-8

These tables list the regulators and environmental conditions examined, a comparison of discovered motifs to literature, the compendium of regulator specificities, characterizations of regulator architectures, a classification of regulator binding behaviours, and motif scoring metrics. (DOC 135 kb)

Supplementary Methods

This file contains additional information about all aspects of experimental procedures used. (DOC 72 kb)

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Harbison, C., Gordon, D., Lee, T. et al. Transcriptional regulatory code of a eukaryotic genome. Nature 431, 99–104 (2004). https://doi.org/10.1038/nature02800

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