Polymer model predicts epigenetic memory and heterogenous dynamics of constitutive heterochromatin domains

The constitutive heterochromatin domains are characterized by enrichment of H3K9me2/3 and a significant presence of heterochromatin protein 1 (HP1a). While HP1a's tendency for liquid-liquid phase separation (LLPS) is observed in vitro, its role in shaping the dynamics and configuration of heterochromatin domains in vivo remains to be elucidated. This study proposes a simplified model incorporating intrinsic HP1a interactions and their affinity towards methylation markers. Using this model, we systematically investigated the system's thermodynamics and dynamics. Our results highlight the critical role of HP1a's homotypic and heterotypic interactions in reinforcing heterochromatin domains. Notably, our approach differs from previous polymer models, as we prioritize mimicking HP1a dynamics in line with in-vivo fluorescence recovery post-photobleaching experiments (FRAP). Using FRAP data on HP1a, our model offers predictions on the chromatin 3D organization and heterochromatin domain sizes, which were validated by Hi-C and high-resolution imaging techniques. Additionally, using our polymer model, we investigated the heterogeneous motion of chromatin inside the heterochromatin domains. Our findings reveal that phase-separated heterochromatin domains exhibit sub-diffusive motion characterized by super-Rousean exponent (a ~ 0.7). This indicates that the binding and unbinding of HP1a could influence individual chromatin segments, moving them from the sub-Rousean regime to the super-Rousean regime. We also highlight the transient nature of constitutive heterochromatin domains, suggesting an irreversible shift from constitutive heterochromatin to euchromatin. This provides a plausible explanation for the sustained stability of these domains post-cell division, even when a significant portion of the epigenetic data is missing. In conclusion, our model suggests that having only half of the epigenetic code, constitutive heterochromatin domains inherently retain their epigenetic memory, leading chromatin to resume its constitutive heterochromatin form post-mitosis.