Topologically associating domains (TADs) are important building blocks of three-dimensional genome architectures. The formation of TADs has been shown to depend on cohesin in a loop-extrusion mechanism. Recently, advances in an image-based spatial genomics technique known as chromatin tracing lead to the discovery of cohesin-independent TAD-like structures, also known as single-cell domains, which are highly variant self-interacting chromatin domains with boundaries that occasionally overlap with TAD boundaries but tend to differ among single cells and among single chromosome copies. Recent computational modeling studies suggest that epigenetic interactions may underlie the formation of the single-cell domains. Here we use chromatin tracing to visualize in female human cells the fine-scale chromatin folding of inactive and active X chromosomes, which are known to have distinct global epigenetic landscapes and distinct population-averaged TAD profiles, with inactive X chromosomes largely devoid of TADs and cohesin. We show that both inactive and active X chromosomes possess highly variant single-cell domains across the same genomic region despite the fact that only active X chromosomes show clear TAD structures at the population level. These X chromosome single-cell domains exist in distinct cell lines. Perturbations of major epigenetic components and transcription mostly do not affect the frequency or strength of the single-cell domains. Increased chromatin compaction of inactive X chromosomes occurs at a length scale above that of the single-cell domains. In sum, this study suggests that single-cell domains are genome architecture building blocks independent of the tested major epigenetic components.

中文翻译：

---

类似 TAD 的单细胞结构域存在于活性和非活性 X 染色体上，并在表观遗传扰动下持续存在


拓扑关联域（TAD）是三维基因组架构的重要构建块。 TAD 的形成已被证明依赖于环挤出机制中的粘连蛋白。最近，基于图像的空间基因组学技术（称为染色质追踪）的进展导致发现了不依赖粘连蛋白的 TAD 样结构，也称为单细胞结构域，它们是高度变异的自相互作用染色质结构域，其边界偶尔会重叠具有 TAD 边界，但在单个细胞和单个染色体拷贝之间往往有所不同。最近的计算模型研究表明，表观遗传相互作用可能是单细胞结构域形成的基础。在这里，我们使用染色质追踪来可视化女性人类细胞中非活性和活性 X 染色体的精细染色质折叠，已知这些 X 染色体具有独特的全局表观遗传景观和独特的群体平均 TAD 谱，其中非活性 X 染色体很大程度上缺乏 TAD 和凝聚力。我们发现，非活性和活性 X 染色体在同一基因组区域都具有高度变异的单细胞结构域，尽管事实上只有活性 X 染色体在群体水平上显示出清晰的 TAD 结构。这些 X 染色体单细胞结构域存在于不同的细胞系中。主要表观遗传成分和转录的扰动大多不会影响单细胞结构域的频率或强度。非活性 X 染色体染色质压缩的增加发生在高于单细胞结构域的长度尺度上。总之，这项研究表明单细胞结构域是独立于测试的主要表观遗传成分的基因组结构构建块。