Whereas folding of genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well understood, how chromatin is folded at finer scales remains largely unexplored in mammals. Here, we overcome some limitations of conventional 3C-based methods by using high-resolution Micro-C to probe links between 3D genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregates TAD regions into various finer-scale structures with distinct regulatory features including stripes, dots, and domains linking promoters-to-promoters (P-P) or enhancers-to-promoters (E-P) and bundle contacts between Polycomb regions. E-P stripes extending from the edge of domains predominantly link co-expressed loci, often in the absence of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts these gene-related folding features without altering higher-order chromatin structures. Our study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation.

中文翻译：

---

解析转录相关哺乳动物染色质折叠的 3D 景观。

尽管现在人们对大规模表观基因组区室和拓扑关联域 (TAD) 的基因组折叠已经有了相对较好的了解，但在哺乳动物中，染色质如何在更精细的尺度上折叠仍然很大程度上尚未被探索。在这里，我们通过使用高分辨率 Micro-C 来探测小鼠干细胞中 3D 基因组组织和转录调控之间的联系，克服了传统 3C 方法的一些局限性。转录因子、辅因子和染色质修饰剂的组合结合在空间上将 TAD 区域分离成具有不同调控特征的各种更精细的结构，包括连接启动子与启动子 (PP) 或增强子与启动子 (EP) 的条纹、点和结构域以及 Polycomb 区域之间的束接触。从结构域边缘延伸的 EP 条纹主要连接共表达位点，通常在没有 CTCF 和粘连蛋白占据的情况下。转录的急性抑制会破坏这些基因相关的折叠特征，而不改变高级染色质结构。我们的研究揭示了以前模糊的更精细的基因组组织，建立了染色质折叠和基因调控之间的功能联系。