Roles of Nuclear Confinement, Excluded Volume, and Persistence on TAD Formations, Chromosome Territories, and Chromatin-Nuclear Envelope Interactions

Abstract

Understanding genome organization is essential for gaining insight into cellular function. Cis chromosome looping interactions, trans chromosome-chromosome interactions, and chromosome-nuclear envelope interactions dictate the overall 3D nuclear architecture. Specifically, looping interactions among different loci of a chromosome lead to formation of topologically associating domains (TADs), whose disruptions are often associated with cellular malfunction; chromosome-chromosome interactions give rise to well-defined chromosomal territories, which play important roles in gene regulation; chromatin-nuclear envelope interactions position specific genes to the nuclear lamina and regulate their expression. While the importance of these structural organizations is well-recognized, the origins of their physical formations are less clear. Here we examine the roles of nuclear confinement, excluded volume, and persistence length in determining these interactions. We generate large ensembles (each of 10∧4 chromatin chains of up to 2,000 structural units) through deep sampling using fractal Monte Carlo. We characterize how the key factors of nuclear confinement, excluded volume, and chromatin stiffness influences these interactions. Specifically, we discuss how TADs and chromosome territories can arise at appropriate nuclear confinement and chromosome persistence length, and how biologically important chromosome-lamina interactions can be identified. We discuss our results in the context of several Hi-C studies.