Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Electrical & Systems Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Sci Rep. 2019 Jul 2;9(1):9526. doi: 10.1038/s41598-019-45457-9.
Mammalian genomes are folded into a hierarchy of compartments, topologically associating domains (TADs), subTADs, and long-range looping interactions. The higher-order folding patterns of chromatin contacts within TADs and how they localize to disease-associated single nucleotide variants (daSNVs) remains an open area of investigation. Here, we analyze high-resolution Hi-C data with graph theory to understand possible mesoscale network architecture within chromatin domains. We identify a subset of TADs exhibiting strong core-periphery mesoscale structure in embryonic stem cells, neural progenitor cells, and cortical neurons. Hyper-connected core nodes co-localize with genomic segments engaged in multiple looping interactions and enriched for occupancy of the architectural protein CCCTC binding protein (CTCF). CTCF knockdown and in silico deletion of CTCF-bound core nodes disrupts core-periphery structure, whereas in silico mutation of cell type-specific enhancer or gene nodes has a negligible effect. Importantly, neuropsychiatric daSNVs are significantly more likely to localize with TADs folded into core-periphery networks compared to domains devoid of such structure. Together, our results reveal that a subset of TADs encompasses looping interactions connected into a core-periphery mesoscale network. We hypothesize that daSNVs in the periphery of genome folding networks might preserve global nuclear architecture but cause local topological and functional disruptions contributing to human disease. By contrast, daSNVs co-localized with hyper-connected core nodes might cause severe topological and functional disruptions. Overall, these findings shed new light into the mesoscale network structure of fine scale genome folding within chromatin domains and its link to common genetic variants in human disease.
哺乳动物基因组折叠成一个层次的隔间，拓扑关联域（TAD），亚区隔和长程环相互作用。TAD 内染色质接触的高阶折叠模式以及它们如何定位到与疾病相关的单核苷酸变异（daSNV）仍然是一个开放的研究领域。在这里，我们使用图论分析高分辨率 Hi-C 数据，以了解染色质域内可能的中尺度网络结构。我们在胚胎干细胞、神经祖细胞和皮质神经元中鉴定出一组表现出强烈核心-外围中尺度结构的 TAD。超连接的核心节点与参与多个环相互作用的基因组片段共定位，并富含结构蛋白 CCCTC 结合蛋白（CTCF）的占据。CTCF 敲低和 CTCF 结合核心节点的计算机删除会破坏核心-外围结构，而细胞类型特异性增强子或基因节点的计算机突变则几乎没有影响。重要的是，与没有这种结构的 TAD 相比，神经精神疾病 daSNV 更有可能定位到折叠成核心-外围网络的 TAD。我们假设，基因组折叠网络外围的 daSNV 可能保留了全局核架构，但会导致局部拓扑和功能中断，从而导致人类疾病。相比之下，与超连接核心节点共定位的 daSNV 可能会导致严重的拓扑和功能中断。总的来说，这些发现揭示了染色质域内精细基因组折叠的中尺度网络结构及其与人类疾病常见遗传变异的联系。
