Statistical Mechanics of Nucleosomes Constrained by Higher-Order Chromatin Structure

TL;DR

This paper develops a thermodynamic model to understand how higher-order chromatin structures influence nucleosome positioning and energetics, revealing the importance of both one- and two-body interactions in chromatin organization.

Contribution

The study introduces a comprehensive thermodynamic model that incorporates finite-size particles and interactions to analyze nucleosome positioning influenced by chromatin structure.

Findings

Both one- and two-body interactions can be extracted from nucleosome density profiles.

A simplified model neglecting two-body interactions can predict sequence determinants.

The minimal model reproduces nucleosome patterns over transcribed regions in vivo.

Abstract

Eukaryotic DNA is packaged into chromatin: one-dimensional arrays of nucleosomes separated by stretches of linker DNA are folded into 30-nm chromatin fibers which in turn form higher-order structures. Each nucleosome, the fundamental unit of chromatin, has 147 base pairs of DNA wrapped around a histone octamer. In order to describe how chromatin fiber formation affects nucleosome positioning and energetics, we have developed a thermodynamic model of finite-size particles with effective nearest-neighbor interactions and arbitrary DNA-binding energies. We show that both one- and two-body interactions can be accurately extracted from one-particle density profiles based on high-throughput maps of in vitro or in vivo nucleosome positions. Although a simpler approach that neglects two-body interactions (even if they are in fact present in the system) can be used to predict sequence determinants of nucleosome positions, the full theory is required to disentangle one- and two-body effects. Finally, we construct a minimal model in which nucleosomes are positioned by steric exclusion and two-body interactions rather than intrinsic histone-DNA sequence preferences. The model accurately reproduces nucleosome occupancy patterns observed over transcribed regions in living cells.