Thermodynamic model of heterochromatin formation through epigenetic regulation

Gene regulation in eukaryotes requires the segregation of silenced genomic regions into densely packed heterochromatin, leaving the active genes in euchromatin regions more accessible. We introduce a model that connects the presence of epigenetically inherited histone marks, methylation at histone 3 lysine-9, to the physical compaction of chromatin fibers via the binding of heterochromatin protein 1 (HP1). Our model demonstrates some of the key physical features that are necessary to explain experimental observations. In particular, we demonstrate that strong cooperative interactions among the HP1 proteins are necessary to see the phase segregation of heterochromatin and euchromatin regions. We also explore how the cell can use the concentration of HP1 to control condensation and under what circumstances there is a threshold of methylation over which the fibers will compact. Finally, we consider how different potential in vivo fiber structures as well as the flexibility of the histone 3 tail can affect the bridging of HP1. Many of the observations that we make about the HP1 system are guided by general thermodynamics principles and thus could play a role in other DNA organizational processes such as the binding of linker histones.