美国斯坦福大学医学院Alistair N. Boettiger团队取得一项新突破。他们发现边界堆叠相互作用促进肢体发育过程中，跨拓扑关联域（TAD）增强子-启动子间的通信。2024年1月18日出版的《自然—遗传学》杂志发表了这项成果。

为了验证跨TAD相互作用的假设，研究人员利用染色质结构的光学重建来揭示发育中小鼠四肢单条染色体上Pitx1基因座的构象。该研究数据支持这样一个模型，即由于环挤压相邻边界会发生堆叠，从而使边界近端顺式元件接触。这种堆叠相互作用也是群体基因图谱中出现结构条纹的原因。通过分子动力学模拟，研究发现增加边界强度有利于形成堆叠边界构象，反过来促进边界旁路。

这项工作对TAD边界的功能进行了修正，既其及促进顺式调控相互作用，也阻止了顺式调控相互作用，并且从适用边界增强子-启动子对中区分出边界相互作用。

据了解，虽然启动子及其增强子经常包含在一个拓扑关联域中，但一些对发育非常重要基因的启动子和增强子却位于不同的拓扑关联域中。关于跨TAD相互作用的分子机制仍有待揭示。

附：英文原文

Title: Boundary stacking interactions enable cross-TAD enhancer–promoter communication during limb development

Author: Hung, Tzu-Chiao, Kingsley, David M., Boettiger, Alistair N.

Issue&Volume: 2024-01-18

Abstract: Although promoters and their enhancers are frequently contained within a topologically associating domain (TAD), some developmentally important genes have their promoter and enhancers within different TADs. Hypotheses about molecular mechanisms enabling cross-TAD interactions remain to be assessed. To test these hypotheses, we used optical reconstruction of chromatin architecture to characterize the conformations of the Pitx1 locus on single chromosomes in developing mouse limbs. Our data support a model in which neighboring boundaries are stacked as a result of loop extrusion, bringing boundary-proximal cis-elements into contact. This stacking interaction also contributes to the appearance of architectural stripes in the population average maps. Through molecular dynamics simulations, we found that increasing boundary strengths facilitates the formation of the stacked boundary conformation, counter-intuitively facilitating border bypass. This work provides a revised view of the TAD borders’ function, both facilitating and preventing cis-regulatory interactions, and introduces a framework to distinguish border-crossing from border-respecting enhancer–promoter pairs.

DOI: 10.1038/s41588-023-01641-2

Source: https://www.nature.com/articles/s41588-023-01641-2