Nonspecific transcription factor-DNA binding influences nucleosome occupancy in yeast

Quantitative understanding of the principles regulating nucleosome occupancy on a genome-wide level is a central issue in eukaryotic genomics. Here, we address this question using budding yeast, Saccharomyces cerevisiae, as a model organism. We perform a genome-wide computational analysis of nonspecific transcription factor (TF)-DNA binding free energy landscape, and compare this landscape with experimentally determined nucleosome binding preferences. We show that DNA regions with enhanced nonspecific TF-DNA binding are statistically significantly depleted of nucleosomes. We suggest therefore that the competition between TFs with histones for nonspecific binding to genomic sequences might be an important mechanism influencing nucleosome-binding preferences in vivo. We also predict that poly(dA:dT) and poly(dC:dG) tracts represent genomic elements with the strongest propensity for nonspecific TF-DNA binding, thus allowing TFs to outcompete nucleosomes at these elements. Our results suggest that nonspecific TF-DNA binding might provide a barrier for statistical positioning of nucleosomes throughout the yeast genome. We predict that the strength of this barrier increases with the concentration of DNA binding proteins in a cell. We discuss the connection of the proposed mechanism with the recently discovered pathway of active nucleosome reconstitution.

💡 Research Summary

The authors investigate how nonspecific transcription factor (TF)–DNA binding influences nucleosome occupancy across the Saccharomyces cerevisiae genome. Using a modified Berg‑von Hippel model, they generate an ensemble of 256 random TFs, each characterized by four base‑specific interaction energies drawn from Gaussian distributions (mean 0, σ = 2 kBT). For every genomic position they slide a 50‑bp window, compute the binding energy U(i) for each TF, and evaluate the partition function Z = ∑ exp