The 11th International Symposium on 3D Genomics

Understanding the mechanisms of cell-fate decision-making in cellular development is pivotal for advancing regenerative medicine and addressing neurodegenerative diseases. Cell-fate decision-making is controlled by gene expression networks, which are in turn influenced by the three-dimensional chromosome structures. During cell-fate decision-making processes, chromosomes progressively adapt their structures to accommodate necessary gene expressions. However, understanding the pathways of chromosome structural dynamics during these transitions remains a significant challenge. In this study, we utilized data-driven coarse-grained molecular dynamics simulations and a physics-based non-equilibrium landscape-switching model to quantify chromosome structural dynamics during cell-state transition processes, including differentiation, reprogramming, transdifferentiation, and cancerogenesis. We quantified the large-scale chromosome structural reorganization pathways during these transitions, and clarified the underlying functional characteristics. Notably, we observed nonmonotonic behaviors in transdifferentiation processes and over-dedifferentiation tendencies in reprogramming processes, from a chromosome structural perspective. Additionally, the chromosome structural dynamical pathways at the scale of topologically associating domains (TADs) exhibited little overlap between forward and reverse directions, in contrast to the ones at the long-range regions, indicating different mechanisms governing these structures. Our study provides a theoretical exploration of cell-fate decision-making from a chromosome structural perspective, offering molecular-level insights into complex cell-state transition processes.

Molecular dynamics simulation,chromosome,genome,cell fate transition,biophysics