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. 2012 Apr 18;102(8):1881-8.
doi: 10.1016/j.bpj.2012.03.044.

Nonspecific protein-DNA binding is widespread in the yeast genome

Ariel Afek  1 , David B Lukatsky
Affiliations

Nonspecific protein-DNA binding is widespread in the yeast genome

Ariel Afek et al. Biophys J. .

Abstract

Recent genome-wide measurements of binding preferences of ~200 transcription regulators in the vicinity of transcription start sites in yeast, have provided a unique insight into the cis-regulatory code of a eukaryotic genome. Here, we show that nonspecific transcription factor (TF)-DNA binding significantly influences binding preferences of the majority of transcription regulators in promoter regions of the yeast genome. We show that promoters of SAGA-dominated and TFIID-dominated genes can be statistically distinguished based on the landscape of nonspecific protein-DNA binding free energy. In particular, we predict that promoters of SAGA-dominated genes possess wider regions of reduced free energy compared to promoters of TFIID-dominated genes. We also show that specific and nonspecific TF-DNA binding are functionally linked and cooperatively influence gene expression in yeast. Our results suggest that nonspecific TF-DNA binding is intrinsically encoded into the yeast genome, and it may play a more important role in transcriptional regulation than previously thought.

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Figures

Figure 1
Figure 1
(A) Average free energy of nonspecific TF-DNA binding per bp, 〈Δf〉 = 〈〈ΔF〉TF〉seq / M, computed within the interval (−384,384) for the two groups of genes selected according to the experimentally measured average TF occupancy in the TSS region: 10% highest TF occupancy in the TSS region (red) and 10% lowest TF occupancy in the TSS region (blue). Each group contains 496 genes. Horizontal bar, marked TSS, on the x axis, shows the corresponding region where the TF occupancy was measured. (B) Similar to (A), but the two groups of genes are selected according to the experimentally measured average TF occupancy in the UAS region. Horizontal bar, marked UAS, on the x axis, shows the corresponding region where the TF occupancy was measured. (C) Correlation between the minimal value of the free energy of nonspecific TF-DNA binding within the TSS regions, Δfmin = min(〈ΔF〉TF) / M, and the average TF occupancy within this region. Genes were binned into 10 bins according to the value of the average TF occupancy. Each point in the graph corresponds to the average, 〈Δfmin〉, for the genes in a given bin plotted as a function of the experimentally measured average TF occupancy for the genes in this bin. (D) Analogous to (C), but for 〈Δfmin〉 computed within the UAS regions, plotted versus the average TF occupancy measured within the UAS regions, as described in C.
Figure 2
Figure 2
(A and B) Number of promoter regions (TSSs and UASs) (black) and coding regions (ORFs) (red) occupied by the number of regulators (i.e., TFs) indicated along the x axis, as computed using the model of nonspecific TF-DNA binding (A) and experimental data from (1). (B) This corresponds to Fig. 2A of (1). In the computational prediction we assumed that a given genomic region is occupied by a given TF if the minimal free energy of nonspecific TF-DNA binding (within this genomic region) is less than the cutoff value of − 1 kBT, and we used 250 TFs in the computation (Materials and Methods). To compute error bars, we divided all genes into four subgroups, and computed the corresponding occupancy separately for each subgroup. The error bars are defined as one standard deviation of the occupancy between the subgroups. Inset in each panel shows the occupancy for the entire set of ∼5000 genes. (C and D) Analogous to the insets in A and B, but with the cumulative TF occupancy computed separately for TSSs and UASs. We used M = 8 for the TF length in all our calculation of the free energy.
Figure 3
Figure 3
(A) Average free energy of nonspecific TF-DNA binding per bp, 〈Δf〉, computed within the interval (−384,384) for the highly confident SAGA-dominated and TFIID-dominated groups of genes, respectively. There are 40 SAGA-dominated, TATA-containing genes and 178 TFIID-dominated, TATA-less, nonribosomal protein genes, respectively (these highly confident groups are taken from (1)). (B) Average free energy of nonspecific TF-DNA binding per bp, 〈Δf〉, computed within the interval (−384,384) for the high and low transcriptional plasticity genes, respectively. There are 732 genes in each group. To compute error bars, we divided each group of genes into five arbitrary subgroups, computed 〈Δf〉 in each of the subgroups, and computed the standard deviation of 〈Δf〉 between the subgroups. Error bars correspond to one standard deviation.
Figure 4
Figure 4
(A) Correlation between the minimal value of the free energy of nonspecific TF-DNA binding in the promoter region, within the interval (−150,0), Δfmin = ΔFmin / M, and the average value of gene expression within this region. All ∼5000 genes were binned into 25 bins according to the level of gene expression. Each point in the graph corresponds to the average, 〈Δfmin〉, for the genes in a given bin plotted as a function of the experimentally measured average level of gene expression for the genes in this bin. (B) Correlation between the computed number of nonspecific TFBNs within the interval (−150,0), and the level of gene expression. A given genomic coordinate is assigned to belong to nonspecific TFBN, if the average free energy of nonspecific TF-DNA binding per nucleotide is smaller than a given cutoff value, Δf < − 0.25 kBT. (C) Correlation between the number of specific TFBSs and the gene expression. The information about specific TFBSs is taken from (33). (D) Correlation between the number of specific TFBSs and the number nonspecific TFBNs. The binning in B–D is preformed as in A.
Figure 5
Figure 5
Analysis of experimental results from (1): Correlation between the average TF occupancy and the level of gene expression for TSS (A), UAS (B), and ORF (C) regions, respectively. Genes were binned into 25 bins according to the level of gene expression. Each point in the graph corresponds to the average, experimental TF occupancy for the genes in a given bin plotted as a function of the experimentally measured, average level of gene expression for the genes in this bin. Correlation between the computed, average value of the minimal free energy of nonspecific TF-DNA binding, 〈Δfmin〉, and the level of gene expression for TSS (D), UAS (E), and ORF (F) regions, respectively. The binning is performed as explained previously.
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