Static Three-Dimensional Structures Determine Fast Dynamics Between Distal Loci Pairs in Interphase Chromosomes

Abstract

Live cell imaging experiments have shown that, although eukaryotic chromosomes are compact, the distal dynamics between enhancers and promoters are unexpectedly rapid and cannot be explained by standard polymer models. The discordance between the compact static chromatin organization (structure) and the relaxation times (dynamics) is a conundrum that violates the expected structure-function relationship. To resolve the puzzle, we developed a theory to predict chromatin dynamics by first calculating the accurate three-dimensional (3D) structure using static Hi-C contact maps or fixed-cell imaging data. The calculated 3D coordinates are used to accurately forecast the two-point dynamics reported in recent experiments that simultaneously monitor chromatin dynamics and transcription. Strikingly, the theory not only predicts the observed fast enhancerpromoter dynamics but also reveals a novel scaling relationship between two-point relaxation time and genomic separation that is in near quantitative agreement with recent experiments. The theory also predicts that cohesin depletion enhances single-locus diffusion. The acceleration of chromatin loci diffusion upon cohesin depletion are explained in terms of structure-based centrality measure used in graph theory. Our framework shows that chromatin dynamics can be predicted based solely on static experimental data, reinforcing the concept that the three-dimensional structure determines their dynamic behavior. The generality of the theory opens new avenues for exploring chromatin dynamics, especially transcriptional dynamics, across different biological contexts.