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.

Compartment-dependent chromatin interaction dynamics revealed by liquid chromatin Hi-C

“…heterochromatic loci and loci tethered to the nuclear periphery vs. loci located in the nuclear interior (Bronshtein et al, 2009;Bronshtein et al, 2015;Hediger et al, 2002;Marshall et al, 1997;Nagashima et al, 2019;Shinkai et al, 2016;Thakar et al, 2006;Therizols et al, 2010).…”

Hi-D: Nanoscale mapping of nuclear dynamics in single living cells

“…However, sparse loci are difficult to place in the context of global chromatin organization and its enduring configurational changes [17]. On the other hand, locally restricted genomic processes can also not be inferred from quantities averaged over the entire nucleus [18,19].…”

3D modeling of chromatin structure: is there a way to integrate and reconcile single cell and population experimental data?

“…76 These advances have been complemented with in silico models of the chromatin or naked DNA fiber, which have been used to mechanistically explain the physics behind conformational changes of the genome. 77,78 Altogether, both imaging and computational modeling could be used to assess the source of structural variability in 3C-derived experiments, which is likely arising from the polymorphic nature of the DNA flexibility and dynamics. This chromatin heterogeneity, already clear between heterochromatin and euchromatin, is a factor that has not yet been integrated in any of the here-discussed modeling strategies, although it has been shown to explain an important part of the observed variability in 3Cbased interaction matrices.…”