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

Three-dimensional genome organization plays a pivotal role in gene regulation. Changes in genomic structure and epigenetic differences can disrupt this organization, leading to variations in phenotype and tissue-specific gene regulation. Previous research primarily examined the effects of these genetic and epigenetic alterations on 3D genome folding using population-wide features, such as topologically associating domains and loops.

However, recent single-cell and live-imaging studies suggest that chromosomes are dynamic, existing as diverse conformations.

In this study, researchers employed an epigenetic-state-informed polymer modeling approach to generate chromosomal conformational ensembles from cell- and tissue-specific epigenomic data. These ensembles successfully replicated experimental Hi-C maps across various cell lines and tissue types. Comparing these ensembles unveiled that while the dynamics remained consistent across cell lines, their folding landscapes differed significantly.

These discrepancies stemmed mainly from cell-line-specific interaction networks within chromatin and were centered around rare, long-lasting contacts.

Modeling a TAD-boundary-disrupting deletion, without adjusting the model parameters, revealed a shift in the chromatin conformational ensemble, transitioning from predominantly insulated to predominantly fused states. The modeling also indicated that the deleted region selectively enhanced active chromatin contacts and disrupted enhancer contacts involving nearby genes.

Lastly, comparing two tissue types from the same donor demonstrated epigenetically driven changes in the chromatin-state interaction networks. These findings highlight chromosomal conformational ensembles as a sensitive indicator of genome reorganization across various genetic and epigenetic contexts.