Polymer physics indicates chromatin folding variability across single-cells results from state degeneracy in phase separation
Polymer physics indicates chromatin folding variability across single-cells results from state degeneracy in phase separation
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DOI：
10.1038/s41467-020-17141-4
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发表时间：
2020-07-03
影响因子：
16.6
通讯作者：
Nicodemi, Mario
中科院分区：
文献类型：
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作者：
Conte, Mattia;Fiorillo, Luca;Nicodemi, Mario
染色体的空间组织具有关键的功能作用，但染色体如何折叠仍然在单分子水平上知之甚少。在这里，我们采用高分子物理模型来研究人HCT 116和IMR90野生型和粘附素缺失细胞中的DNA位点。单分子结构的模型预测对单细胞成像数据进行验证，提供的证据表明，染色体结构是由聚合物相分离的热力学机制控制的，从而染色质自组装在分离的小球中的染色质因子，包括CTCF和粘附素的组合相互作用。单分子构象的热力学简并性导致了TAD类接触模式的广泛的结构和时间可变性。球状体建立稳定的环境，在那里特定的接触比随机接触更受欢迎。内聚素耗尽将相分离反转成随机折叠状态，消除平均相互作用模式。总体而言，小球相分离似乎是一个强大的，但可逆的染色质组织的随机性和特异性共存的机制。在单个DNA分子水平上染色质折叠的分子和物理机制仍然知之甚少。在这里，作者使用聚合物建模研究正常和凝聚素耗尽细胞中两个2Mb宽的DNA位点的构象，并提供证据表明，所研究的位点的结构是由聚合物相分离的热力学机制控制的，从而染色质自组装在分离的小球中。
The spatial organization of chromosomes has key functional roles, yet how chromosomes fold remains poorly understood at the single-molecule level. Here, we employ models of polymer physics to investigate DNA loci in human HCT116 and IMR90 wild-type and cohesin depleted cells. Model predictions on single-molecule structures are validated against single-cell imaging data, providing evidence that chromosomal architecture is controlled by a thermodynamics mechanism of polymer phase separation whereby chromatin self-assembles in segregated globules by combinatorial interactions of chromatin factors that include CTCF and cohesin. The thermodynamics degeneracy of single-molecule conformations results in broad structural and temporal variability of TAD-like contact patterns. Globules establish stable environments where specific contacts are highly favored over stochastic encounters. Cohesin depletion reverses phase separation into randomly folded states, erasing average interaction patterns. Overall, globule phase separation appears to be a robust yet reversible mechanism of chromatin organization where stochasticity and specificity coexist. The molecular and physical mechanisms underlying chromatin folding at the single DNA molecule level remain poorly understood. Here, the authors use polymer modeling to investigate the conformations of two 2Mb-wide DNA loci in normal and cohesin depleted cells, and provide evidence that the architecture of the studied loci is controlled by a thermodynamics mechanism of polymer phase separation whereby chromatin self-assembles in segregated globules.