Epigenome-informed Polymer Modeling Reveals Chromosome Folding Landscapes across Distinct Genetic and Epigenetic Contexts

Epigenetic-state-informed polymer modeling reconstructs cell- and tissue-specific chromosomal conformational ensembles that reproduce experimental Hi-C maps and reveal divergent folding landscapes.

• Why it matters: Population-averaged 3D genome features miss how dynamic, heterogeneous conformations respond to genetic structural variation and epigenetic differences across contexts.
• What they did: The framework generates conformational ensembles from cell- and tissue-specific epigenomic data, reproducing Hi-C maps across cell lines and tissue types, then compares folding landscapes and interaction networks.
• The result: Folding dynamics are conserved but landscapes diverge due to cell-line-specific chromatin-state interaction networks concentrated in rare, long-lived contacts; a TAD-boundary-disrupting deletion shifts insulated-to-fused states and rewires enhancer contacts, with tissue-to-tissue rewiring from the same donor.

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