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

Vinayak Vinayak, Ramin Basir, Rosela Golloshi, Joshua Toth, Lucas Sant’Anna, Melike Lakadamyali, Rachel Patton McCord and Vivek B. Shenoy ()
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Vinayak Vinayak: University of Pennsylvania
Ramin Basir: University of Pennsylvania
Rosela Golloshi: Johns Hopkins University School of Medicine
Joshua Toth: University of Pennsylvania
Lucas Sant’Anna: University of Pennsylvania
Melike Lakadamyali: University of Pennsylvania
Rachel Patton McCord: University of Tennessee
Vivek B. Shenoy: University of Pennsylvania

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59001-z

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