What controls nucleosome positions?

Abstract

The DNA of eukaryotic genomes is wrapped in nucleosomes, which strongly distort and occlude the DNA from access to most DNA-binding proteins. An understanding of the mechanisms that control nucleosome positioning along the DNA is thus essential to understanding the binding and action of proteins that carry out essential genetic functions. New genome-wide data on in vivo and in vitro nucleosome positioning greatly advance our understanding of several factors that can influence nucleosome positioning, including DNA sequence preferences, DNA methylation, histone variants and post-translational modifications, higher order chromatin structure, and the actions of transcription factors, chromatin remodelers and other DNA-binding proteins. We discuss how these factors function and ways in which they might be integrated into a unified framework that accounts for both the preservation of nucleosome positioning and the dynamic nucleosome repositioning that occur across biological conditions, cell types, developmental processes and disease.

Figure 1

A unified framework for nucleosome positioning. Here, we present an illustration of our unified view, in which nucleosome positions are explained by the combined effect of both static, condition-invariant inputs such as nucleosome and TF sequence preferences (d–f), and dynamic, condition-dependent inputs such as the concentrations of histones (not shown) and TFs, the composition of histones, and the methylation status of the genome (a–c). Two different TFs are colored blue and red; different histones are colored yellow (H2A), orange (H2B) or turquoise (H3, H4); histone variants are outlined with a dashed line; PTMs are shown as red triangles; resulting nucleosomes are colored green; methylated CpGs are shown as blue lines through the grey DNA; and an occluded TF-binding site is indicated by a red X. Each input influences the positions of nucleosomes according to specific rules. The model that integrates these inputs assumes that nucleosomes equilibrate their positions, such that every possible configuration of nucleosomes and TFs on the DNA is sampled (g; shown is a small subset of the possible configurations). The probability that the system will be in any one configuration, P(c), is computed from the statistical weight of each configuration, which depends in turn on the concentrations of histones and input TFs and their affinities to the DNA sites they occupy in the configuration, taking into account the effects of the higher order chromatin structure of the configuration. The affinity of every nucleosome in a configuration is computed from its DNA sequence preferences, histone composition, and methylation status of the underlying DNA. Overlaps between two molecules in any one configuration are not allowed owing to steric hindrance and, thus, both nucleosome–nucleosome and nucleosome-factor competition is modeled. Finally, although our focus here is on the determinants of nucleosome organization, we note that the distribution of molecule-binding configurations will partly dictate the behavior of various functional outputs, including transcription, recombination, DNA repair and replication.