Dynamic Nucleosome Movement Provides Structural Information of Topological Chromatin Domains in Living Human Cells

Abstract

The mammalian genome is organized into submegabase-sized chromatin domains (CDs) including topologically associating domains, which have been identified using chromosome conformation capture-based methods. Single-nucleosome imaging in living mammalian cells has revealed subdiffusively dynamic nucleosome movement. It is unclear how single nucleosomes within CDs fluctuate and how the CD structure reflects the nucleosome movement. Here, we present a polymer model wherein CDs are characterized by fractal dimensions and the nucleosome fibers fluctuate in a viscoelastic medium with memory. We analytically show that the mean-squared displacement (MSD) of nucleosome fluctuations within CDs is subdiffusive. The diffusion coefficient and the subdiffusive exponent depend on the structural information of CDs. This analytical result enabled us to extract information from the single-nucleosome imaging data for HeLa cells. Our observation that the MSD is lower at the nuclear periphery region than the interior region indicates that CDs in the heterochromatin-rich nuclear periphery region are more compact than those in the euchromatin-rich interior region with respect to the fractal dimensions as well as the size. Finally, we evaluated that the average size of CDs is in the range of 100-500 nm and that the relaxation time of nucleosome movement within CDs is a few seconds. Our results provide physical and dynamic insights into the genome architecture in living cells.\n\nAuthor SummaryThe mammalian genome is partitioned into topological chromatin domains (CDs) in the living cell nuclei. Gene expression is highly regulated within CDs according to their structure, whereas chromatin itself is highly dynamic. This raises the following question: how is the CD structure in such dynamic chromatin? We developed a conceptual framework that unifies chromatin dynamics and structure. Using a polymer model with a fractal domain structure in a viscoelastic medium, we analytically show that nucleosome movement is subdiffusive and depends on CD structure. Hence, structural information can be extracted based on nucleosome movement in living cells with single-particle tracking experiments. This framework provides physical insights into the relationship between dynamic genome organization and gene expression.