Abstract
Because DNA packaging in nucleosomes modulates its accessibility to transcription factors (TFs), unraveling the causal determinants of nucleosome positioning is of great importance to understanding gene regulation. Although there is evidence that intrinsic sequence specificity contributes to nucleosome positioning, the extent to which other factors contribute to nucleosome positioning is currently highly debated. Here we obtained both in vivo and in vitro reference maps of positions that are either consistently covered or free of nucleosomes across multiple experimental data-sets in Saccharomyces cerevisiae. We then systematically quantified the contribution of TF binding to nucleosome positiong using a rigorous statistical mechanics model in which TFs compete with nucleosomes for binding DNA. Our results reconcile previous seemingly conflicting results on the determinants of nucleosome positioning and provide a quantitative explanation for the difference between in vivo and in vitro positioning. On a genome-wide scale, nucleosome positioning is dominated by the phasing of nucleosome arrays over gene bodies, and their positioning is mainly determined by the intrinsic sequence preferences of nucleosomes. In contrast, larger nucleosome free regions in promoters, which likely have a much more significant impact on gene expression, are determined mainly by TF binding. Interestingly, of the 158 yeast TFs included in our modeling, we find that only 10–20 significantly contribute to inducing nucleosome-free regions, and these TFs are highly enriched for having direct interations with chromatin remodelers. Together our results imply that nucleosome free regions in yeast promoters results from the binding of a specific class of TFs that recruit chromatin remodelers.
Highlights
The genomes of all eukaryotic organisms are packaged into nucleosomes, which are the fundamental units of chromatin, each composed of approximately 147 base pairs of DNA wrapped around a histone octamer
To obtain energy matrices for the large majority of sequence-specific transcription factors (TFs) in S. cerevisiae we used a collection of 158 weight matrices (WMs) that we curated previously [32] and that are based on a combination of chromatin immunoprecipitation (ChIP)-chip and in vitro binding data
It is generally accepted that the packaging of DNA by nucleosomes in eukaryotes can modulate the accessibility of TFs to their cognate sites and thereby have major effects on gene regulation
Summary
The genomes of all eukaryotic organisms are packaged into nucleosomes, which are the fundamental units of chromatin, each composed of approximately 147 base pairs (bp) of DNA wrapped around a histone octamer. Recent developments in technologies for measuring chromatin marks by chromatin immunoprecipitation (ChIP) on microarrays (ChIP-Chip) or by sequencing (ChIP-seq) have enabled the construction of genome-wide maps of nucleosome positions and modifications at high resolution across various conditions. These experimental data have revealed that nucleosomes are not uniformly distributed across the genome but rather that transcription start and termination sites are relatively depleted of nucleosomes [1,2]. It has long been known that barriers in the DNA can cause nucleosomes to be ‘statistically positioned’ relative to such barriers, introducing a periodic pattern of nucleosome occupancy on both sides of the barrier [7]. Recent work suggests that nucleosome occupancy patterns around TSSs could at least partly be explained by such statistical positioning [8]
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