Mammalian chromosomes fold into arrays of megabase-sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher-order organization remains elusive. Here, we investigate TAD higher-order interactions with Hi-C through neuronal differentiation and show that they form a hierarchy of domains-within-domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree-like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.

中文翻译：

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染色体的分级折叠和重组与细胞分化的转录变化有关。

哺乳动物染色体折叠成兆碱基大小的拓扑关联结构域 (TAD) 阵列，这些结构域排列成跨越多个兆碱基基因组 DNA 的隔室。TAD 具有通常是细胞类型特异性的内部子结构，但它们的高阶组织仍然难以捉摸。在这里，我们通过神经元分化研究了 TAD 与 Hi-C 的高阶相互作用，并表明它们形成了跨基因组尺度的域内域 (metaTAD) 的层次结构，延伸到整个染色体的范围。我们发现无论细胞类型如何，树状的层次结构都能很好地捕捉到 TAD 的相互作用。metaTAD 树结构与遗传、表观基因组和表达特征相关，分化过程中的结构树重排与转录状态变化有关。