As an essential and fundamental process of life, cell development involves large‐scale reorganization of the 3D genome architecture, which forms the basis of gene regulation. Here, a landscape‐switching model is developed to explore the microscopic chromosomal structural origin of embryonic stem cell (ESC) differentiation and somatic cell reprogramming. It is shown that chromosome structure exhibits significant compartment‐switching in the unit of topologically associating domain. It is found that the chromosome during differentiation undergoes monotonic compaction with spatial repositioning of active and inactive chromosomal loci toward the chromosome surface and interior, respectively. In contrast, an overexpanded 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. 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 is suggested. The theoretical model herein including the non‐equilibrium effects, draws a picture of the highly irreversible cell differentiation and reprogramming processes, in line with the experiments. The predictions provide a physical understanding of cell differentiation and reprogramming from the chromosomal structural and dynamical perspective and can be tested by future experiments.

中文翻译：

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细胞分化和重编程的微观染色体结构和动态起源

作为生命必不可少的基本过程，细胞发育涉及3D基因组架构的大规模重组，这构成了基因调控的基础。在这里，开发了一种景观转换模型，以探索胚胎干细胞（ESC）分化和体细胞重编程的微观染色体结构起源。结果表明，染色体结构在拓扑关联域单元中表现出明显的区室转换。发现分化过程中的染色体经历了单调压缩，其中活性和非活性染色体基因座分别朝着染色体表面和内部空间定位。相比之下，染色体过度扩增 在重新编程过程中，观察到了其在染色体表面表现出基因座的普遍定位并擦除了体细胞中形成的结构特征。建议从ESC到终末分化细胞的早期独特分化途径，在Waddington景观上引起ESC分化的早期分叉。本文的理论模型包括非平衡效应，与实验相吻合，描绘出了高度不可逆的细胞分化和重编程过程。这些预测从染色体的结构和动力学角度提供了对细胞分化和重编程的物理理解，可以通过未来的实验进行验证。建议从ESC到终末分化细胞的早期独特分化途径，在Waddington景观上引起ESC分化的早期分叉。本文的理论模型包括非平衡效应，与实验相吻合，描绘了高度不可逆的细胞分化和重编程过程。这些预测从染色体的结构和动力学角度提供了对细胞分化和重编程的物理理解，可以通过未来的实验进行验证。建议从ESC到终末分化细胞的早期独特分化途径，在Waddington景观上引起ESC分化的早期分叉。本文的理论模型包括非平衡效应，与实验相吻合，描绘出了高度不可逆的细胞分化和重编程过程。这些预测从染色体的结构和动力学角度提供了对细胞分化和重编程的物理理解，可以通过未来的实验进行验证。根据实验绘制了高度不可逆的细胞分化和重编程过程的图片。这些预测从染色体的结构和动力学角度提供了对细胞分化和重编程的物理理解，可以通过未来的实验进行验证。根据实验绘制了高度不可逆的细胞分化和重编程过程的图片。这些预测从染色体的结构和动力学角度提供了对细胞分化和重编程的物理理解，可以通过未来的实验进行验证。