Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant'Angelo, 80126, Naples, Italy.
Berlin Institute for Medical Systems Biology, Max-Delbrück Centre (MDC) for Molecular Medicine, Berlin, Germany.
Nat Commun. 2022 Jul 13;13(1):4070. doi: 10.1038/s41467-022-31856-6.
Loop-extrusion and phase-separation have been proposed as mechanisms that shape chromosome spatial organization. It is unclear, however, how they perform relative to each other in explaining chromatin architecture data and whether they compete or co-exist at the single-molecule level. Here, we compare models of polymer physics based on loop-extrusion and phase-separation, as well as models where both mechanisms act simultaneously in a single molecule, against multiplexed FISH data available in human loci in IMR90 and HCT116 cells. We find that the different models recapitulate bulk Hi-C and average multiplexed microscopy data. Single-molecule chromatin conformations are also well captured, especially by phase-separation based models that better reflect the experimentally reported segregation in globules of the considered genomic loci and their cell-to-cell structural variability. Such a variability is consistent with two main concurrent causes: single-cell epigenetic heterogeneity and an intrinsic thermodynamic conformational degeneracy of folding. Overall, the model combining loop-extrusion and polymer phase-separation provides a very good description of the data, particularly higher-order contacts, showing that the two mechanisms can co-exist in shaping chromatin architecture in single cells.
环挤出和相分离已被提议作为塑造染色体空间组织的机制。然而，目前尚不清楚它们在解释染色质结构数据方面彼此的相对作用，以及它们在单分子水平上是竞争还是共存。在这里，我们将基于环挤出和相分离的聚合物物理模型与同时在单个分子中起作用的两种机制的模型进行比较，以对抗在 IMR90 和 HCT116 细胞中的人类基因座中可用的多重 FISH 数据。我们发现，不同的模型可以重现整体 Hi-C 和平均多重显微镜数据。单分子染色质构象也得到了很好的捕捉，特别是基于相分离的模型，这些模型更好地反映了所考虑基因组基因座的球体内的实验报告的分离及其在细胞间的结构变异性。这种可变性与两个主要的并发原因一致：单细胞表观遗传异质性和折叠的内在热力学构象简并性。总体而言，结合环挤出和聚合物相分离的模型很好地描述了数据，特别是高级别接触，表明这两种机制可以在单个细胞中共同作用以形成染色质结构。
