Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  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)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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. 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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ernest Fraenkel or Richard A. Young.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02800

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing