Nonspecific Transcription-Factor-DNA Binding Influences Nucleosome Occupancy in Yeast

Abstract

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 the 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.

Control of transcriptional pausing by biased thermal fluctuations on repetitive genomic sequences

“…We thus investigated the sequence context effect on RNAP pausing between the true and false PIEs. As described below and in our previous studies (24)(25)(26)(27)(28)(29), we have previously revealed that nonconsensus repetitive DNA sequence elements in the vicinity of a consensus protein-binding motif statistically enhance the protein binding to its "site." This finding led us to hypothesize that a similar context effect could provide the mechanism responsible for the genome-wide regulation of RNAP pausing at PIE motifs.…”

“…We have characterized the mechanism of this context effect (24)(25)(26)(27)(28)(29) as an extension of the concept for nonspecific protein-DNA binding introduced by von Hippel and coworkers (30)(31)(32)(33) 40 y ago. Briefly, nonspecific protein-DNA binding (i.e., protein sliding on DNA) represents an electrostatically dominated mechanism, and it was usually assumed that it is uniform (on average) and entirely nonspecific outside of short specific recognition motifs along the genomic DNA (33).…”

“…experimental knowledge of protein-DNA binding affinity; rather, it uses DNA sequences as the only input (24)(25)(26)(27)29). Briefly, nonspecific DNA sequences enriched in certain repetitive sequence patterns such as homo-oligonucleotide tracts can modulate the spectrum of protein-DNA binding energy fluctuations (24,28).…”

Mechanisms of Protein Search for Targets on DNA: Theoretical Insights

“…Thus, our theoretical calculations make surprising predictions that the sequence heterogeneity almost always lead to faster protein search for targets on DNA despite the fact that it lowers the effective protein-DNA binding affinity. [43][44][45][46] And the stronger the contribution of the 1D search modes, the more relevant will be the effect of sequence heterogeneity.…”

RNA polymerase II pausing as a context-dependent reader of the genome

“…First, gene promoters are known to serve as center points, relative to which the nucleosomes are positioned (Mavrich et al 2008a; Afek et al 2011). However, nucleosome-free regions (NFRs) are also well defined in yeast, which appear to lack ubiquitous promoter-proximal pausing (Rhee and Pugh, 2012), indicating that it is not pausing, but the promoter itself that may be responsible for establishing the NFR.…”