Modeling the Effects of Structure and Epigenetic Modifications in Heterochromatin Condensation

Abstract

Proper gene silencing requires physically restricting access to those genes, such as in condensed nuclear regions called heterochromatin. Cells epigenetically inherit which genomic regions are heterochromatin at least in part through methylation of histone 3 at lysine-9 (H3K9). We have developed a thermodynamic model of heterochromatin condensation via bridging interactions of heterochromatin protein 1 (HP1) bound to nearby nucleosomes. HP1 binds at H3K9, with enhanced binding when the site is methylated. After taking low energy chromatin fiber structures from a model based on the energetics of the wrapped DNA, we find the distances between HP1 binding sites on multiple nearby fibers. Dimerization and interaction of HP1 is known to occur in vivo, so nearby bound HP1 have a favorable coupling energy which enhances the interaction between these chromatin fibers. We have fine tuned our model to experimental measurements of HP1 binding to offer predictions about the effects of fiber structure and lysine-9 methylation on fiber condensation. After comparing a range of low energy fiber structures, we find that similarly compact chromatin structures prefer to associate together. In addition, we show that the differing amount of methylation in chromatin can enhance local concentrations of HP1 similar to in vivo measurements. These results demonstrate how local chromatin structure and epigenetic modifications can impact large-scale chromatin organization in the nucleus.