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Comparative Study
. 2008 Jul;18(7):1084-91.
doi: 10.1101/gr.076059.108. Epub 2008 Apr 30.

Two strategies for gene regulation by promoter nucleosomes

Itay Tirosh  1 , Naama Barkai
Affiliations
Comparative Study

Two strategies for gene regulation by promoter nucleosomes

Itay Tirosh et al. Genome Res. 2008 Jul.

Abstract

Chromatin structure is central for the regulation of gene expression, but its genome-wide organization is only beginning to be understood. Here, we examine the connection between patterns of nucleosome occupancy and the capacity to modulate gene expression upon changing conditions, i.e., transcriptional plasticity. By analyzing genome-wide data of nucleosome positioning in yeast, we find that the presence of nucleosomes close to the transcription start site is associated with high transcriptional plasticity, while nucleosomes at more distant upstream positions are negatively correlated with transcriptional plasticity. Based on this, we identify two typical promoter structures associated with low or high plasticity, respectively. The first class is characterized by a relatively large nucleosome-free region close to the start site coupled with well-positioned nucleosomes further upstream, whereas the second class displays a more evenly distributed and dynamic nucleosome positioning, with high occupancy close to the start site. The two classes are further distinguished by multiple promoter features, including histone turnover, binding site locations, H2A.Z occupancy, expression noise, and expression diversity. Analysis of nucleosome positioning in human promoters reproduces the main observations. Our results suggest two distinct strategies for gene regulation by chromatin, which are selectively employed by different genes.

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Figures

Figure 1.
Figure 1.
Correlation between nucleosome occupancy and transcription regulation. Nucleosome occupancy was compared with three aspects of transcription regulation: mRNA abundance (blue), transcriptional plasticity (average of the squared log2 expression ratio) to a range of perturbation (green), and sensitivity to chromatin regulation (red). These three measures were normalized by subtracting their means and dividing by their standard deviations. (A) Genes were ordered by their average occupancy at the 150 bp upstream of the TSS, and a sliding window (window size of 500 genes) is shown for the three measures of transcription regulation. (B) Correlations between nucleosome occupancy at each position (from −400 to 0, relative to the TSS) and the three measures of transcription regulation.
Figure 2.
Figure 2.
Two patterns of nucleosome occupancy. (A) The pattern of nucleosome occupancy at each promoter was summarized by two values: the average occupancy at −100 to 0 (proximal region), and that at −400 to −150 (distal region). For each of these values, the genes were sorted and divided into eight equal bins. We examined the number of genes in each combination of bins for the two values and compared it with the expected number if the two values were independent. Colors specify the log2 of the ratio between the observed and expected number of genes in each combination of bins: (red) positive values (enrichment), (green) negative values (depletion). (B) Two classes were defined based on their enrichment: low occupancy at the proximal region and high occupancy at the distal region (DPN), and high occupancy at the proximal region and low occupancy at the distal region (OPN).
Figure 3.
Figure 3.
Differential properties of the two promoter classes. (A) Average values of properties that quantify the levels and variability of gene expression and the turnover of promoter H3 histones are shown for DPN genes (blue) and OPN genes (red). Values in each property were normalized to mean zero and standard deviation one. (B) Distribution of the maximal nucleosome occupancy within predicted nucleosomes (filled circles) and the distribution of the minimal nucleosome occupancy within predicted linker DNA (empty circles), for DPN (blue) and OPN (red) genes; distribution of the average occupancy within each element (rather than maximum or minimum) gives similar results (Supplemental Fig. 4). (C) Frequency of genes with multiple binding sites, TATA box, and histone variant H2A.Z is shown for DPN (blue), OPN (red), and all (white) genes. (D) Distribution of the promoter positions of transcription factor binding sites and TATA boxes (dashed lines) in the two classes. Error bars in A and C were calculated by bootstrapping.
Figure 4.
Figure 4.
Analyses of human promoters reproduce the distinction between promoter classes. The ratio between nucleosome occupancy at the TSS-proximal and -distal regions is correlated with transcriptional plasticity among the eight yeast (A) or human (B) promoter classes. Lines indicate the linear least-squares fit. Red and blue circles represent clusters corresponding to OPN and DPN, respectively. (C) Human OPN promoters (red bars) are enriched with CpG-poor promoters and TATA boxes, are depleted in H2A.Z, and have lower peak-to-trough ratios compared with human DPN promoters (blue bars). Similar results were obtained in analysis of human nucleosome positions from high-throughput sequencing (Supplemental Fig. 11; Schones et al. 2008). In addition, the ratio of human nucleosome occupancy was also significantly correlated with binding of CTCF and several histone H3 methylations (Supplemental Fig. 12; Barski et al. 2007).
Figure 5.
Figure 5.
A model for nucleosome organization at low-plasticity and high-plasticity promoters. (A) Average mRNA levels are correlated with overall nucleosome occupancy, whereas transcriptional plasticity is correlated with the relative pattern of nucleosome occupancy. Genes were sorted by overall nucleosome occupancy (Y-axis) or relative pattern of nucleosome occupancy (proximal/distal; X-axis), and divided to eight bins of equal sizes. The average normalized mRNA abundance (left) or transcriptional plasticity (right) is shown for each of the 64 bins. (B) The architecture of two promoter classes. Low-plasticity (DPN) promoters tend to have well-positioned nucleosomes and a strong NFR directly upstream of the TSS. High-plasticity (OPN) genes have “fuzzy” nucleosomes whose positions are heterogenic and dynamic, perhaps as a consequence of competition with transcription factors. Binding sites are distal to the TSS, and binding of regulators to these sites may influence nucleosome positions proximal to the TSS, thus affecting transcription. (Brown circles) Transcription factors in a binding equilibrium to their binding sites (BS), (ovals) nucleosomes, (curves) pattern of nucleosome occupancy.
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