Spatial confinement is a major determinant of the folding landscape of human chromosomes.
Bottom Line: 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 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.
Affiliation: Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA.Show MeSH
Mentions: To examine the effects of the spatial confinement, we generated independent ensembles of 10 000 C-SAC chains of length N inside a sphere D. Here N is varied from 50, 100 and then up to 1000, with increments of 100. The sphere diameter D takes the value of 2.5, 5.0 and 7.5 μm, in addition to 1.5 μm. We independently generated different ensembles of 10 000 C-SAC chains at each of the combination of N and D values. Altogether, we have 4 × 11 = 44 independent ensembles of 10 000 C-SAC chains for calculating contact probability. We used partial chains of length s from the ensemble of 10 000 chains of N = 1000 of different D for the calculation of mean-square spatial distance R2(s), following the approach used in the FISH studies (69). We found that both exponents α and ν increase with D (Figure 2A and B). Furthermore, chromatin chains tend to adopt more open conformation as D increases. At the same time, the leveling-off effect at larger genomic distances disappears (Figure 2B). Further clustering of chromatin structures (see Supplementary Information) at different nuclear sizes showed that even with the smallest nucleus size of D = 1.5 μm, there exists a substantial amount of open chromatin structures (10.9%), while the compact structures and in-between structures are 18.6 and 70.5% of the population, respectively. As the size of the nucleus increases, the percentage of open-like structures in the population increases. These results therefore suggest that nuclear size is a major factor in influencing the overall folding landscape of chromatin, via modulation of the spatial confinement scale D.
Affiliation: Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA.