Genome-wide chromosome architecture prediction reveals biophysical principles underlying gene structure.

Classical observations suggest a connection between 3D gene structure and function, but testing this hypothesis has been challenging due to technical limitations. To explore this, we developed epigenetic highly predictive heteromorphic polymer (e-HiP-HoP), a model based on genome organization principles to predict the 3D structure of human chromatin. We defined a new 3D structural unit, a "topos," which represents the regulatory landscape around gene promoters. Using GM12878 cells, we predicted the 3D structure of over 10,000 active gene topoi and stored them in the 3DGene database. Data mining revealed folding motifs and their link to Gene Ontology features. We computed a structural diversity score and identified influential nodes-chromatin sites that frequently interact with gene promoters, acting as key regulators. These nodes drive structural diversity and are tied to gene function. e-HiP-HoP provides a framework for modeling high-resolution chromatin structure and a mechanistic basis for chromatin contact networks that link 3D gene structure with function.