Quantifying Chromosome Structural Reorganizations during Differentiation, Reprogramming, and Transdifferentiation

We developed a nonequilibrium model to study chromosome structural reorganizations within a simplified cell developmental system. From the chromosome structural perspective, we predicted that the neural progenitor cell is on the neural developmental path and very close to the transdifferentiation path from the fibroblast to the neuron cell. We identified an early bifurcation of stem cell differentiation processes and the cell-of-origin-specific reprogramming pathways. Our theoretical results are in good agreement with available experimental evidence, promoting future applications of our approach.

Figure 1

An illustrative landscape-switching model for chromosome structural reorganizations during the cell-state transition processes.

Figure 2

Chromosome structural reorganizations during differentiation, reprogramming, and transdifferentiation. (a) The chromosome contact probability evolving along with time during the cell-state transitions. The contact maps of the ESC, NPC, Fibro, and Neuron cells are derived from the experimental Hi-C data. The contact maps at $t=0.1\tau$, $\tau$, $10\tau$, and $100\tau$ of each transition are calculated, where $\tau$ is the unit of MD time. The ideograms of the chromosome segment used in our study (chr14: 20.5–106.1 Mb) are annotated by the compartment status at the corresponding cell state. The contact map is at the 100-kb resolution. (b) The correlation of the distance-corrected contact probability map during the transition with the ones at the initial (solid line) and final (dashed line) states of the transition, as well as the NPC (purple line) [78]. The correlation is indicated by the coefficient of determination $R^2$.

Figure 3

Quantified chromosome structural reorganization pathways during differentiation, reprogramming, and transdifferentiation from the TADs perspective. The quantified pathways are shown in the PCA plots of the insulation score profiles projected at the first two PCs for (a) differentiation, (b) reprogramming, (c) conversion to the Fibro cell, (d) conversion to the Neuron cell, (e) deformation from the Fibro cell, and (f) deformation from the Neuron cell. The averaged pathways are collected and shown in (g). The shadow regions indicate the error bars of the averaged pathways from the bootstrapping analysis. The scheme illustrating the six cell-state transitions is shown in (h).

Figure 4

The same as Fig. 3, but the PCA plots are done for contact probability ${\log }_2(P_{\mathrm{obs}}/P_{\exp })$.