Population Properties and Complex Folding Behavior of Chromosome Arise from Spatial Confinement of Self-Avoiding Chromatin Chains

Abstract

Global architecture of cell nucleus and the spatial organization of chromatin play important roles in gene expression and nuclear function. Single-cell imaging and chromosome conformation capture-based techniques provide information on chromosome conformations and their spatial organization. Here we describe a chromatin model called constrained self-avoiding chromatin (C-SAC) for studying chromatin structures. With a novel sampling technique, we can generate a large ensemble of chromatin chains with the appropriate physical properties and spatial confinement. We show that randomly folded chromosome in the confined nuclear volume give rise to the experimentally observed higher-order architecture of human chromosomes, including the average scaling behavior, leveling-off effect, the formation of topological domains, chromosome-to-chromosome and cell-to-cell variability, as well as highly enriched interactions via insulator proteins. Our results point to an emerging picture of the folding landscape of chromatin scaffold that changes with nucleus size, and suggest that the overall structure of human chromosome is dictated by the spatial confinement of the cell nucleus and the excluded volume effect. Biochemically mediated interactions do not change the average properties of chromosomes, but profoundly modulate structural details based on the existing structural scaffold.