Center for Comparative Biomedicine, State Key Laboratory of Medical Genomics, Institute of Systems Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Bioessays. 2024 Oct;46(10):e2400121. doi: 10.1002/bies.202400121. Epub 2024 Aug 21.
Topologically associating domain (TAD) boundaries are the flanking edges of TADs, also known as insulated neighborhoods, within the 3D structure of genomes. A prominent feature of TAD boundaries in mammalian genomes is the enrichment of clustered CTCF sites often with mixed orientations, which can either block or facilitate enhancer-promoter (E-P) interactions within or across distinct TADs, respectively. We will discuss recent progress in the understanding of fundamental organizing principles of the clustered CTCF insulator codes at TAD boundaries. Specifically, both inward- and outward-oriented CTCF sites function as topological chromatin insulators by asymmetrically blocking improper TAD-boundary-crossing cohesin loop extrusion. In addition, boundary stacking and enhancer clustering facilitate long-distance E-P interactions across multiple TADs. Finally, we provide a unified mechanism for RNA-mediated TAD boundary function via R-loop formation for both insulation and facilitation. This mechanism of TAD boundary formation and insulation has interesting implications not only on how the 3D genome folds in the Euclidean nuclear space but also on how the specificity of E-P interactions is developmentally regulated.
拓扑关联域（TAD）边界是基因组 3D 结构中 TAD 的侧翼边缘，也称为隔离邻域。哺乳动物基因组中 TAD 边界的一个显著特征是富含聚集的 CTCF 位点，这些位点的取向通常混合，它们可以分别阻止或促进同一或不同 TAD 内的增强子-启动子（E-P）相互作用。我们将讨论在理解 TAD 边界处聚集的 CTCF 绝缘子代码的基本组织原则方面的最新进展。具体来说，内倾和外倾的 CTCF 位点通过不对称地阻止不适当的 TAD 边界穿越黏合蛋白环挤出，作为拓扑染色质绝缘子发挥作用。此外，边界堆积和增强子聚类促进了跨越多个 TAD 的长距离 E-P 相互作用。最后，我们提供了一个统一的机制，通过 R 环形成来解释 RNA 介导的 TAD 边界功能，该机制既具有绝缘作用，也具有促进作用。这种 TAD 边界形成和绝缘的机制不仅对 3D 基因组在欧几里得核空间中的折叠方式有重要意义，而且对 E-P 相互作用的特异性如何在发育过程中受到调节也有重要意义。
