Polymer model integrates imaging and sequencing to reveal how nanoscale heterochromatin domains influence gene expression
Year: 2025
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Health and Human Services, National Institutes of Health, Materials Research Science and Engineering Center, Harvard University, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Biomedical Imaging and Bioengineering, Division of Materials Research, Division of Civil, Mechanical and Manufacturing Innovation
Awards: G1013684226, G1051554911, G155958390, Materials Research Science and Engineering Center, Pathological consequences of altered tissue mechanics in fibrosis, G2361442177, G2407097552, G2567800894, G2567842326, G3200575684, G342638498, G4212146726, Collaborative Research: Multiscale and Multiphasic Modeling of Single and Collective Migration in Fibrous Extracellular Matrices, G5462003112, G5743373210, G588188242, Integration of elasticity, viscosity, and plasticity in cellular mechanosensing, G643866923, G6994470052, G7125181322, Mechanical determinants of organ-selective metastatic colonization, dormancy and outgrowth, G71947432, G7537657417, An integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skin, G7947965700, G8137833789, G889968654, G9000060776, G9000095374, G9000106290, Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease
OpenAlex ID: W4409725784