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 expression. Comparative genomics has recently been used to identify potential cis-regulatory sequences within the yeast genome on the basis of phylogenetic conservation, 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.

Figure 1

Discovering binding-site specificities for yeast transcriptional regulators. a, Cis-regulatory sequences likely to serve as recognition sites for transcriptional regulators were identified by combining information from genome-wide location data, phylogenetically conserved sequences and previously published evidence, as described in Supplementary Methods. The compendium of regulatory sequence motifs can be found in Supplementary Table 3. b, Selected sequence specificities that were rediscovered and were newly discovered are shown. The total height of the column is proportional to the information content of the position, and the individual letters have a height proportional to the product of their frequency and the information content.

Figure 2

Drafting the yeast transcriptional regulatory map. a, Portions of chromosomes illustrating locations of genes (grey rectangles) and conserved DNA sequences (coloured boxes) bound in vivo by transcriptional regulators. b, Combining binding data and sequence conservation data. The diagram depicts all sequences matching a motif from our compendium (top), all such conserved sequences (middle) and all such conserved sequences bound by a regulator (bottom). c, Regulator binding site distribution. The red line shows the distribution of distances from the start codon of open reading frames to binding sites in the adjacent upstream region. The green line represents a randomized distribution.

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. For the purposes of illustration, not all sites are shown and the scale is approximate. Additional information can be found in Supplementary Tables 4–6.

Figure 4

Environment-specific use of the transcriptional regulatory code. Four patterns of genome-wide binding behaviour are depicted on the left, where transcriptional regulators are represented by coloured circles and are placed above and below a set of target genes/promoters. The lines between the regulators and the target genes/promoters represent binding events. Specific examples of the environment-dependent behaviours are depicted on the right. Coloured circles represent regulators and coloured boxes represent their DNA binding sequences within specific promoter regions. We note that regulators might exhibit different behaviours when different pairs of conditions are compared.