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.
Highlights
Human cells must accommodate ∼6 billion base pairs of deoxyribonucleic acid (DNA) in a small nucleus with a diameter of 6–20 m [1]
We examined the effects of spatial confinement on chromosome folding using the constrained self-avoiding chromatin (C-SAC) model
Since the mass density of chromatin and how it varies in different loci and different chromosomes are unknown, the regime that the exponents are extracted are not directly comparable by genomic distance to the experimental data
Summary
Human cells must accommodate ∼6 billion base pairs of deoxyribonucleic acid (DNA) in a small nucleus with a diameter of 6–20 m [1]. Understanding the spatial organization of chromatin within the cell nucleus is key to gaining insights into the mechanism of gene activities, nuclear functions and maintenance of cellular epigenetic states [2]. Fluorescence in situ hybridization (FISH) and chromosome conformation capture (3C) and related techniques revealed a wealth of information about spatial chromatin structures across different genomic regions for a variety of cell types []. A key outcome of FISH experiments is the relationship between the mean-square spatial distance, R2, and the genomic distance, s, of two chromosome loci [5–69]. The leveling-off effects indicate that each chromosome is confined to a volume much smaller than the nuclear volume [69]. This reflects the requirement that chromosomes must fit into localized territories [11]
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