Uncovering High-Resolution Organization of Genomic Loci using Experimentally Informed Polymer Model

The functionality of an organism depends on gene expression patterns, which are governed by the hierarchical organization of the genome. Numerous efforts, leveraging both polymer physics-based models and experimental imaging technologies, have sought to elucidate the structure-function relationship of chromatin fibers. However, a major challenge remains: the intrinsically multi-scale nature of chromatin organization, which has yet to be fully explored. Here, we present an experimentally informed, polymer physics-based model capable of reconstructing chromatin structural ensembles by integrating low-resolution contact data with MNase-derived nucleosome positioning information. We applied this model to multiple human genomic loci. Our analysis uncovered distinct structural features associated with active and inactive chromatin states, providing key insights into the relationship between genomic organization and transcriptional activity. These findings offer a promising framework for understanding genome structure-function relationships and their implications in developmental disorders and gene misregulation-related diseases.