Abstract

As an essential and fundamental process of life, cell development involves large-scale reorganization of the three-dimensional genome architecture, which forms the basis of gene regulation. Here, we develop a landscape-switching model to explore the microscopic chromosomal structural origin of the embryonic stem cell (ESC) differentiation and the somatic cell reprogramming. We show that chromosome structure exhibits significant compartment-switching in the unit of topologically associating domain. We find that the chromosome during differentiation undergoes monotonic compaction with spatial re-positioning of active and inactive chromosomal loci towards the chromosome surface and interior, respectively. In contrast, an over-expanded chromosome, which exhibits universal localization of loci at the chromosomal surface with erasing the structural characteristics formed in the somatic cells, is observed during reprogramming. We suggest an early distinct differentiation pathway from the ESC to the terminally differentiated cell, giving rise to early bifurcation on the Waddington landscape for the ESC differentiation. Our theoretical model including the non-equilibrium effects, draws a picture of the highly irreversible cell differentiation and reprogramming processes, in line with the experiments. The predictions from our model provide a physical understanding of cell differentiation and reprogramming from the chromosomal structural and dynamical perspective and can be tested by future experiments.