Polymer model integrates imaging and sequencing to reveal how nanoscale heterochromatin domains influence gene expression.

Chromatin organization regulates gene expression, with nanoscale heterochromatin domains playing a fundamental role. Their size varies with microenvironmental stiffness and epigenetic interventions, but how these factors regulate their formation and influence transcription remains unclear. To address this, we developed a sequencing-informed copolymer model that simulates chromatin evolution through diffusion and active epigenetic reactions. Our model predicts the formation of nanoscale heterochromatin domains and quantifies how domain size scales with epigenetic reaction rates, showing that epigenetic and compaction changes primarily occur at domain boundaries. We validated these predictions via Hi-C and super-resolution imaging of hyperacetylated melanoma cells and identified differential expression of metastasis-related genes through RNA-seq. We validated our findings in hMSCs, where epigenetic reaction rates respond to microenvironmental stiffness. Conclusively, our simulations reveal that heterochromatin domain boundaries regulate gene expression and epigenetic memory. These findings demonstrate how external cues drive chromatin organization and transcriptional memory in development and disease.