LAUSR

Significance Predicting how epigenetic marks control the 3D organization of the genome is key to understanding how these marks regulate gene expression. We show that a physical model of a chromosome with experimentally measured local interactions segregates into euchromatin- and heterochromatin-like phases. The model reproduces many of the features of the large-scale organization of the chromosome as measured by Hi-C. Our work provides an estimate of the amount of epigenetic marking needed to segregate a gene into heterochromatin. We use a chromosome-scale simulation to show that the preferential binding of heterochromatin protein 1 (HP1) to regions high in histone methylation (specifically H3K9me3) results in phase segregation and reproduces features of the observed Hi-C contact map. Specifically, we perform Monte Carlo simulations with one computational bead per nucleosome and an H3K9me3 pattern based on published ChIP-seq signals. We implement a binding model in which HP1 preferentially binds to trimethylated histone tails and then oligomerizes to bridge together nucleosomes. We observe a phase reminiscent of heterochromatin—dense and high in H3K9me3—and another reminiscent of euchromatin—less dense and lacking H3K9me3. This segregation results in a plaid contact probability map that matches the general shape and position of published Hi-C data. Analysis suggests that a roughly 20-kb segment of H3K9me3 enrichment is required to drive segregation into the heterochromatic phase.