Epigenetic Memory Achieved Through Chromatin-Induced Phase Separation

Chromatin structure is a key determinant of gene expression and epigenetic inheritance. It relies on the post-translational modification of histones, the three-dimensional organization of nucleosomal DNA and interactions between chromatin components. To investigate interplays between these elements, we employed molecular dynamics simulations that integrated polymer modeling with enzymatic reactions on nucleosomes catalyzed by read-write enzymes. We explicitly modeled the diffusible heterochromatic nucleosome reader Swi6 (an HP1 homolog) that engages in homotypic and heterotypic interactions, undergoes and induces conformational changes upon binding to heterochromatic nucleosomes, and facilitates the targeted recruitment of histone deacetylases. The model revealed bistable epigenetic states with a silent state associated to the phase separation of heterochromatic domain condensates. Condensates were supported by Swi6 in a dosage-dependent manner that can be recapitulated in an analytic mean-field approximation. Our model of heterochromatic condensates further showed how a heterochromatic region can induce silencing of another region through spatial proximity in three dimensions. Moreover, extensions of the model suggested a mechanism for how negative feedback from antisilencing factors, here fission yeast Epe1, could confine the spreading of the heterochromatic state by acting on the surface of the condensates, altogether leading to epigenetically stable, spatially restricted chromatin states.