Quantitative test of the barrier nucleosome model for statistical positioning of nucleosomes up- and downstream of transcription start sites

TL;DR

This study quantitatively tests the barrier nucleosome model for nucleosome positioning around transcription start sites in yeast, using a physics-based model to explain observed patterns and boundary conditions.

Contribution

It provides a quantitative analysis confirming that the barrier nucleosome model, with specific boundary conditions, explains nucleosome positioning patterns around TSSs.

Findings

Both sides of NFR are described by the same physical model with different boundary conditions.

The +1 nucleosome is typically directly positioned, upstream nucleosomes are statistically positioned.

Boundary conditions influence nucleosome distribution over ~1000 bp range.

Abstract

The positions of nucleosomes in eukaryotic genomes determine which parts of the DNA sequence are readily accessible for regulatory proteins and which are not. Genome-wide maps of nucleosome positions have revealed a salient pattern around transcription start sites, involving a nucleosome-free region (NFR) flanked by a pronounced periodic pattern in the average nucleosome density. While the periodic pattern clearly reflects well-positioned nucleosomes, the positioning mechanism is less clear. A recent experimental study by Mavrich et al. argued that the pattern observed in S. cerevisiae is qualitatively consistent with a `barrier nucleosome model', in which the oscillatory pattern is created by the statistical positioning mechanism of Kornberg and Stryer. On the other hand, there is clear evidence for intrinsic sequence preferences of nucleosomes, and it is unclear to what extent these sequence preferences affect the observed pattern. To test the barrier nucleosome model, we quantitatively analyze yeast nucleosome positioning data both up- and downstream from NFRs. Our analysis is based on the Tonks model of statistical physics which quantifies the interplay between the excluded-volume interaction of nucleosomes and their positional entropy. We find that although the typical patterns on the two sides of the NFR are different, they are both quantitatively described by the same physical model, with the same parameters, but different boundary conditions. The inferred boundary conditions suggest that the first nucleosome downstream from the NFR (the +1 nucleosome) is typically directly positioned while the first nucleosome upstream is statistically positioned via a nucleosome-repelling DNA region. These boundary conditions, which can be locally encoded into the genome sequence, significantly shape the statistical distribution of nucleosomes over a range of up to ~1000 bp to each side.