Department of Chemistry, University of Texas at Austin, Austin, Texas, 78712, USA.
Department of Materials Science, University of Illinois, Urbana, Illinois, 61801, USA.
Nat Commun. 2023 Mar 1;14(1):1150. doi: 10.1038/s41467-023-36412-4.
The principles that govern the organization of genomes, which are needed for an understanding of how chromosomes are packaged and function in eukaryotic cells, could be deciphered if the three-dimensional (3D) structures are known. Recently, single-cell imaging techniques have been developed to determine the 3D coordinates of genomic loci in vivo. Here, we introduce a computational method (Distance Matrix to Ensemble of Structures, DIMES), based on the maximum entropy principle, with experimental pairwise distances between loci as constraints, to generate a unique ensemble of 3D chromatin structures. Using the ensemble of structures, we quantitatively account for the distribution of pairwise distances, three-body co-localization, and higher-order interactions. The DIMES method can be applied to both small and chromosome-scale imaging data to quantify the extent of heterogeneity and fluctuations in the shapes across various length scales. We develop a perturbation method in conjunction with DIMES to predict the changes in 3D structures from structural variations. Our method also reveals quantitative differences between the 3D structures inferred from Hi-C and those measured in imaging experiments. Finally, the physical interpretation of the parameters extracted from DIMES provides insights into the origin of phase separation between euchromatin and heterochromatin domains.
如果知道三维（3D）结构，就可以破译控制基因组组织的原则，这些原则对于理解染色体在真核细胞中如何包装和发挥功能至关重要。最近，已经开发出单细胞成像技术来确定体内基因组基因座的 3D 坐标。在这里，我们介绍了一种基于最大熵原理的计算方法（距离矩阵到结构集合，DIMES），该方法以基因座之间的实验成对距离作为约束条件，生成独特的 3D 染色质结构集合。使用结构集合，我们定量地解释了成对距离、三体共定位和高阶相互作用的分布。DIMES 方法可应用于小范围和染色体尺度成像数据，以定量描述不同长度尺度上形状的异质性和波动程度。我们结合 DIMES 开发了一种摄动方法，以预测结构变化引起的 3D 结构变化。我们的方法还揭示了从 Hi-C 推断的 3D 结构与在成像实验中测量的结构之间的定量差异。最后，从 DIMES 中提取的参数的物理解释提供了对常染色质和异染色质域之间相分离起源的深入了解。
