Insights into the Cell Fate Decision-making Processes from Chromosome Structural Reorganizations

The cell fate decision-making process, which provides the capability of a cell transition to a new cell type, involves the reorganizations of 3D genome structures. Currently, the high temporal resolution picture of how the chromosome structural rearrangements occur and further influence the gene activities during the cell-state transition is still challenging to acquire. Here, we study the chromosome structural reorganizations during the cell-state transitions among the pluripotent embryonic stem cell, the terminally differentiated normal cell, and the cancer cell using a nonequilibrium landscape-switching model implemented in the molecular dynamics simulation. We quantify the chromosome (de)compaction pathways during the cell-state transitions and find that the two pathways having the same destinations can merge prior to reaching the final states. The chromosomes at the merging states have similar structural geometries but can differ in long-range compartment segregation and spatial distribution of the chromosomal loci and genes, leading to cell-type-specific transition mechanisms. We identify the irreversible pathways of chromosome structural rearrangements during the forward and reverse transitions connecting the same pair of cell states, underscoring the critical roles of nonequilibrium dynamics in the cell-state transitions. Our results contribute to the understanding of the cell fate decision-making processes from the chromosome structural perspective.