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Transcriptional regulatory code of a eukaryotic genome


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.

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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).

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