Deciphering the dynamical chromosome structural reorganizations in human neural development

Abstract

Understanding the mechanisms of cell-fate determination in neural development is pivotal for advancing regenerative medicine and addressing neurodegenerative diseases. Cell-fate determination is controlled by the underlying gene expression networks, which are further regulated by the three-dimensional chromosome structures. During neural development, chromosomes progressively adapt their structures to accommodate the requisite gene expressions. However, elucidating the pathways of chromosome structural dynamics during these transitions remains a grand challenge. In this study, we employed the data-driven coarse-grained molecular dynamics simulations, coupled with the nonequilibrium landscape-switching model, to quantify the chromosome structural dynamics during human neural development. We focused on a simplified human neural developmental system, comprising of cell differentiation, reprogramming, and transdifferentiation among the neural progenitor cell (NPC), the glia cell, and the neuron cell. We identified significant large-scale chromosome structural reorganizations during cell-state transitions. From the chromosome structural perspective, the transdifferentiation processes between the glia and neuron cells exhibited nonmonotonic behaviors characterized by an initial increase followed by a subsequent decrease in cell stemness. The transdifferentiation appeared to share the same routes of differentiation after passing through the NPC. Additionally, our findings revealed that the chromosome structural dynamical pathways at the scale of topologically associating domains exhibited little overlap, in contrast to the ones at the long-range regions. This suggests that the active, ATP-driven molecular processes play dominant roles in modulating topologically associating domain (TAD) structures, while the compartmental segregation in chromosomes is primarily governed by the passive phase separation. Our study offers a theoretical exploration of neural cell-fate determination from the chromosome structural perspective, paving a way for potential applications in neuroregeneration. Published by the American Physical Society 2024