Spatial confinement is a major determinant of the folding landscape of human chromosomes

Abstract

The global architecture of the 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 a wealth of information on the spatial organization of chromosomes. However, a mechanistic model that can account for all observed scaling behaviors governing long-range chromatin interactions is missing. Here we describe a model called constrained self-avoiding chromatin (C-SAC) for studying spatial structures of chromosomes, as the available space is a key determinant of chromosome folding. We studied large ensembles of model chromatin chains with appropriate fiber diameter, persistence length and excluded volume under spatial confinement. We show that the equilibrium ensemble of randomly folded chromosomes in the confined nuclear volume gives rise to the experimentally observed higher-order architecture of human chromosomes, including average scaling properties of mean-square spatial distance, end-to-end distance, contact probability and their chromosome-to-chromosome variabilities. Our results indicate that the overall structure of a human chromosome is dictated by the spatial confinement of the nuclear space, which may undergo significant tissue- and developmental stage-specific size changes.

Confinement-Induced Glassy Dynamics in a Model for Chromosome Organization

“…Hence, we expect that P (s) ∼ s −α with α = 1.5 [17,32]. In the case of strong confinement, however, P (s) ∼ s −1 in the range of s/a ∼ O(10) for N = 300, similar to the scaling observed in the Hi-C analysis of the chromosome in interphase [3,33]. The range of s −1 -scaling increases as the extent of confinement increases (Fig.1d).…”

Multiscale simulation of DNA

“…Introduction of higher level of detail can be achieved by the intermediate chain-of-beads approach, which involves two features: small-scale chromatin properties and overall genome organization based on experimental results, for example from Hi-C [165], FISH [168] or cryo-EM [159] Hi-C contacts) [171][172][173]. Constant improvement in Hi-C techniques [166] and the recent irruption of ultra-resolution fluorescence microscopy in the field [174] suggests that there is room for th 'int m diat ' a ach t improve thelevel of resolution, with the long-range objective to reach atleastnucleosome-level resolution.…”

“…Finally, worth to mention is the work by Müller et al Within the pure intermediate methods the objective is to move to much longer models than those accessible to the bottom-up approach, relying on the experimental data to correct the intrinsic limitations of the simple physical model used [159,165,168]. Quite surprisingly, very simple polymer models such as C-SAC [173] are able to reproduce well some experimental details on chromatin compaction such as the observed scaling behavior of contact probability vs. genomic distance in interphase human chromatin just by introducing restrictions on the nuclear volume. Similarly, Gehlen et al [172] were able to reproduce overall structural architecture of yeast chromatin by putting spatial constraints involving the positions of centromers, telomeres and nucleolus.…”

Shape Transitions and Chiral Symmetry Breaking in the Energy Landscape of the Mitotic Chromosome

“…A complete understanding of chromosomal organization is challenging since the condensation of the chromosome into its dense mitotic form permits many different orderings and phase transitions. Owing to the large scale of the chromosome, we also can expect interesting non-equilibrium glassy dynamics and possible kinetic control of structure formation [5][6][7][8][9][10][11][12][13].Structural models of the mitotic chromosome have been proposed, including the radial loop model [4], the chromatin network model [14] and the hierarchical folding model [3]. These models often highlight the biologically specific role of protein molecules but the intrinsic properties of the DNA as a long highly helical molecule must also be at work.…”

“…A complete understanding of chromosomal organization is challenging since the condensation of the chromosome into its dense mitotic form permits many different orderings and phase transitions. Owing to the large scale of the chromosome, we also can expect interesting non-equilibrium glassy dynamics and possible kinetic control of structure formation [5][6][7][8][9][10][11][12][13].…”