聚合物模拟框架从 Hi-C 数据中分离大肠杆菌染色体的特异性折叠相互作用
Disentangling polymer confinement from specific-folding interactions reveals the drivers of Escherichia coli chromosome organization
研究团队开发了一个基于聚合物的模拟框架，用于在大肠杆菌中区分特异性折叠相互作用（SFIs）与非特异性的聚合物压缩。研究发现，由 300 000 条随机聚合物构型构成的零模型即可重现 Hi-C 数据中的整体染色体组织，说明大部分 Hi-C 信号反映的是受限体积内的通用聚合物行为。将零模型预测与实验 Hi-C 数据对比后，仅分离出不足 7% 的 SFIs，并据此生成 20 000 个单细胞构象的特异折叠集合，重现了染色体互作结构域和单细胞异质性。
来源：Nucleic Acids Research · doi.org
The three-dimensional organization of the bacterial chromosome is critical for gene regulation. Chromosome conformation capture (Hi-C) has enabled genome-wide mapping of chromosomal folding, yet ensemble-averaged contact maps entangle biologically specific-folding interactions (SFIs) with nonspecific polymer compaction and mask single-cell heterogeneity. Here, we developed a polymer-based simulation framework in Escherichia coli to address these limitations. We found that a null model of 300 000 random polymer configurations recapitulated the global chromosomal organization observed in Hi-C data, establishing that most Hi-C signals reflect generic polymer behavior in a confined volume. Contrasting null-model predictions with experimental Hi-C data isolated a small subset of SFIs (<7%) and generated a specific-fold ensemble of 20 000 single-cell conformations that reproduced chromosomal interaction domains and single-cell heterogeneity. SFIs were enriched in the ter region, reduced nucleoid accessibility, colocalized with cryptic prophages, and depleted in positively supercoiled regions. H-NS and MatP emerged as major chromosome-wide and local determinants of SFIs, respectively. Furthermore, high-SFI regions correlated with stress-adaptive genes, whereas low-SFI regions harbored housekeeping genes. Together, our results established that a small number of biologically encoded SFIs superimposed on a polymer background shape the E. coli chromosome and gene expression, providing a quantitative framework for dissecting chromosome architecture and function.