Widespread link between DNA-packing density distribution and TAD boundary locations

Abstract

Abstract DNA is heterogeneously packaged into chromatin, which are further organized into Topologically associating domains (TADs) with sharp boundaries. The locations of TAD boundaries are critical for gene regulation. Here, we investigate whether the distribution of DNA-packing density along chromatin has an impact on the TAD boundary locations. We develop a polymer-physics-based model that utilizes DNA-accessibility data to parameterize DNA-packing density along chromosomes, treating them as heteropolymers, and simulates the stochastic folding of these heteropolymers within the nucleus to yield a conformation ensemble. Such an ensemble accurately reproduces a subset (over 36%) of TAD boundaries in human cells at a genome-wide scale, as confirmed by Hi-C data. Additionally, it faithfully reproduces the spatial distance matrices of 2-Mb genomic regions as provided by FISH experiments. Furthermore, our model demonstrates that utilizing solely DNA-accessibility data as input is already adequate to predict the emergence and disappearance of crucial TADs during early T cell differentiation. These results establish a link between DNA-packing density distribution and TAD boundary positions, complementing existing models and uncovering aspects of genome organization beyond molecular processes such as loop extrusion and phase separation. In the future, integrating these models offers promising avenues for understanding intricate genome organization.