High-throughput sequencing reveals a simple model of nucleosome energetics

TL;DR

This study uses high-throughput sequencing data and an analytical model to understand how DNA sequence influences nucleosome positioning and energetics, revealing that simple nucleotide composition differences largely explain occupancy patterns.

Contribution

It introduces a novel analytical framework linking nucleosome occupancy to sequence-specific free energies, highlighting the primary role of mono- and dinucleotide content in nucleosome positioning.

Findings

Nucleosome occupancy correlates with mono- and dinucleotide content.

Periodic dinucleotide patterns influence nucleosome positioning.

Experimental artifacts may bias high-throughput nucleosome maps.

Abstract

We use nucleosome maps obtained by high-throughput sequencing to study sequence specificity of intrinsic histone-DNA interactions. In contrast with previous approaches, we employ an analogy between a classical one-dimensional fluid of finite-size particles in an arbitrary external potential and arrays of DNA-bound histone octamers. We derive an analytical solution to infer free energies of nucleosome formation directly from nucleosome occupancies measured in high-throughput experiments. The sequence-specific part of free energies is then captured by fitting them to a sum of energies assigned to individual nucleotide motifs. We have developed hierarchical models of increasing complexity and spatial resolution, establishing that nucleosome occupancies can be explained by systematic differences in mono- and dinucleotide content between nucleosomal and linker DNA sequences, with periodic dinucleotide distributions and longer sequence motifs playing a secondary role. Furthermore, similar sequence signatures are exhibited by control experiments in which genomic DNA is either sonicated or digested with micrococcal nuclease in the absence of nucleosomes, making it possible that current predictions based on high-throughput nucleosome positioning maps are biased by experimental artifacts.