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. 2022 May 10:19:1-14.
doi: 10.2142/biophysico.bppb-v19.0018. eCollection 2022.

Epigenetic-structural changes in X chromosomes promote Xic pairing during early differentiation of mouse embryonic stem cells

Tetsushi Komoto  1 , Masashi Fujii  1 , Akinori Awazu  1   2
Affiliations

Epigenetic-structural changes in X chromosomes promote Xic pairing during early differentiation of mouse embryonic stem cells

Tetsushi Komoto et al. Biophys Physicobiol. .

Abstract

X chromosome inactivation center (Xic) pairing occurs during the differentiation of embryonic stem (ES) cells from female mouse embryos, and is related to X chromosome inactivation, the circadian clock, intra-nucleus architecture, and metabolism. However, the mechanisms underlying the identification and approach of X chromosome pairs in the crowded nucleus are unclear. To elucidate the driving force of Xic pairing, we developed a coarse-grained molecular dynamics model of intranuclear chromosomes in ES cells and in cells 2 days after the onset of differentiation (2-day cells) by considering intrachromosomal epigenetic-structural feature-dependent mechanics. The analysis of the experimental data showed that X-chromosomes exhibit the rearrangement of their distributions of open/closed chromatin regions on their surfaces during cell differentiation. By simulating models where the excluded volume effects of closed chromatin regions are stronger than those of open chromatin regions, such rearrangement of open/closed chromatin regions on X-chromosome surfaces promoted the mutual approach of the Xic pair. These findings suggested that local intrachromosomal epigenetic features may contribute to the regulation of cell species-dependent differences in intranuclear architecture.

Keywords: X chromosome; Xic pairing; embryonic stem cells.

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Figures

Figure 1
Figure 1
Intragenomic distributions and ratios of A-, B-, and M-regions on autosomal and X chromosomes in ES cells and 2-day cells: (a) Example distribution profiles of A/B compartments in two biological replicates and those of A-, B-, and M-regions on chromosomes 1 and X (4×107 bp to 5×107 bp). The M-regions were broadly distributed on X chromosomes of ES cells but showed decreased distributions in 2-day cells. (b) Ratios of A-, B-, and M-regions on each chromosome. Both ES cells and 2-day differentiated cells contained few M-regions on autosomes. The ratio of the M-region on the X chromosome was larger in ES cells and dramatically reduced in 2-day cells. The NA region is the region with no Hi-C data, which was expected to correspond to the region containing the centromere or telomere.
Figure 2
Figure 2
Intrachromosomal spatial distributions of open and closed chromatin regions. (a) NDA, NDB, and NDM of chromosome 1 and the X chromosome in ES cells and 2-day cells. Insets show typical distributions of A- (green), B- (red), and M-regions (blue) on chromosome surfaces, as observed from one viewpoint (see data in Supplementary Table S1). (b) Average RPD values and 95% confidence intervals (error bars) for all chromosomes. Stars between two neighboring DCC values indicated that two average RPD values were significantly different (p<0.01 using Welch’s test; p values are plotted in Supplementary Figure S3). (c) RDB+M–A at DCC>1.2 for each chromosome. (d) CL for each chromosome.
Figure 3
Figure 3
Snapshots of simulations of the coarse-grained blob chain model of chromosomes. (a, b) Examples of snapshots of blob chain models of chromosome 1 (a) and the X chromosome (b) in the ES cell model (see Supplementary Table S5 for results of other chromosomes in both the ES cell and 2-day cell models). Green, red, and blue spheres indicate A-blob, B-blob, and M-blob, respectively. (c, d) Snapshot of all chromosomes in the ES cell model (c) and positioning of two X chromosomes (d). Blob chains with different colors indicate models of different chromosomes.
Figure 4
Figure 4
Probability distributions of the distance between the Xic pair and between homologous chromosomes. (a) Average and 95% confidence interval (error bar) of probability distributions of the distance between the pair of blobs containing Xic in the ES cell and 2-day cell models (left), and p values (Welch’s test) between two probability values of the two models at each distance (right). (b, c) The same plots as the left for (a) between an X chromosome pair (b) and between a chromosome 1 pair (c). The average and 95% confidence interval were evaluated using results from 30 simulations for each model. Distances with asterisks indicate that differences in probability values between the two models were significant (p<0.05 using Welch’s test; see also Supplementary Figures S5 and S6).
Figure 5
Figure 5
Illustrations showing the simple 1-d lattice-block model consisting of soft and rigid blocks providing an intuitive understanding of the mechanism by which X chromosomes tend to exhibit mutual approach in 2-day cell model. (a) The model consists of nine sites with edge walls, two yellow blocks, and two green blocks. It is assumed that the width of each block=2 sites, and that two soft blocks can overlap with each other by half (1 site). (b) Illustrations of all states when all blocks were assumed to be rigid blocks. The number of all states was obtained as 30, and the number of states that two green blocks contact (or overlap) with each other was obtained as 12. Therefore, the probability that two green blocks contact (or overlap) with each other was estimated to be 12/30=0.4. (c) Illustrations of all states when green and yellow blocks were respectively assumed as soft and rigid blocks, and two green blocks overlap with each other. By the combination of states in (b) and (c), when the increase in the potential energy with the overlap between two green blocks was assumed to be U, the probability that two green blocks make contact or overlap with each other was estimated as (12+30e–U/kBT)/(30+30e–U/kBT)>0.4 (kB is the Boltzmann constant, and T is the temperature). This probability approaches 42/60=0.7 for U→0. These facts suggested that when two green blocks were soft, like the X chromosomes in the 2-day cell model, mutual approaches occur more frequently than when the green blocks were rigid like the X chromosomes in the ES cell model.
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