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Conformational state switching and pathways of chromosome dynamics in cell cycle.

ABSTRACT: The cell cycle is a process and function of a cell with different phases essential for cell growth, proliferation, and replication. It depends on the structure and dynamics of the underlying DNA molecule, which underpins the genome function. A microscopic structural-level understanding of how a genome or its functional module chromosome performs the cell cycle in terms of large-scale conformational transformation between different phases, such as the interphase and the mitotic phase, is still challenging. Here, we develop a non-equilibrium, excitation-relaxation energy landscape-switching model to quantify the underlying chromosome conformational transitions through (de-)condensation for a complete microscopic understanding of the cell cycle. We show that the chromosome conformational transition mechanism from the interphase to the mitotic phase follows a two-stage scenario, in good agreement with the experiments. In contrast, the mitotic exit pathways show the existence of an over-expanded chromosome that recapitulates the chromosome in the experimentally identified intermediate state at the telophase. We find the conformational pathways are heterogeneous and irreversible as a result of the non-equilibrium dynamics of the cell cycle from both structural and kinetic perspectives. We suggest that the irreversibility is mainly due to the distinct participation of the ATP-dependent structural maintenance of chromosomal protein complexes during the cell cycle. Our findings provide crucial insights into the microscopic molecular structural and dynamical physical mechanism for the cell cycle beyond the previous more macroscopic descriptions. Our non-equilibrium landscape framework is general and applicable to study diverse non-equilibrium physical and biological processes such as active matter, differentiation/development, and cancer.

SUBMITTER: Chu X

PROVIDER: S-EPMC7376616 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Direct conversion of one differentiated cell type into another is defined as cell transdifferentiation. In avoidance of forming pluripotency, cell transdifferentiation can reduce the potential risk of tumorigenicity, thus offering significant advantages over cell reprogramming in clinical applications. Until now, the mechanism of cell transdifferentiation is still largely unknown. It has been well recognized that cell transdifferentiation is determined by the underlying gene expression regulation, which relies on the accurate adaptation of the chromosome structure. To dissect the transdifferentiation at the molecular level, we develop a nonequilibrium landscape-switching model to investigate the chromosome structural dynamics during the state transitions between the human fibroblast and neuron cells. We uncover the high irreversibility of the transdifferentiation at the local chromosome structural ranges, where the topologically associating domains form. In contrast, the pathways in the two opposite directions of the transdifferentiation projected onto the chromosome compartment profiles are highly overlapped, indicating that the reversibility vanishes at the long-range chromosome structures. By calculating the contact strengths in the chromosome at the states along the paths, we observe strengthening contacts in compartment A concomitant with weakening contacts in compartment B at the early stages of the transdifferentiation. This further leads to adapting contacts toward the ones at the embryonic stem cell. In light of the intimate structure-function relationship at the chromosomal level, we suggest an increase of "stemness" during the transdifferentiation. In addition, we find that the neuron progenitor cell (NPC), a cell developmental state, is located on the transdifferentiation pathways projected onto the long-range chromosome contacts. The findings are consistent with the previous single-cell RNA sequencing experiment, where the NPC-like cell states were observed during the direct conversion of the fibroblast to neuron cells. Thus, we offer a promising microscopic and physical approach to study the cell transdifferentiation mechanism from the chromosome structural perspective.

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Conformational state switching and pathways of chromosome dynamics in cell cycle.

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