Centre de Biologie Structurale, CNRS UMR 5048, INSERM U1054, Univ Montpellier, Montpellier, France.
IGMM, CNRS, Univ Montpellier, Montpellier, France.
Nat Genet. 2021 Apr;53(4):477-486. doi: 10.1038/s41588-021-00816-z. Epub 2021 Apr 1.
Acquisition of cell fate is thought to rely on the specific interaction of remote cis-regulatory modules (CRMs), for example, enhancers and target promoters. However, the precise interplay between chromatin structure and gene expression is still unclear, particularly within multicellular developing organisms. In the present study, we employ Hi-M, a single-cell spatial genomics approach, to detect CRM-promoter looping interactions within topologically associating domains (TADs) during early Drosophila development. By comparing cis-regulatory loops in alternate cell types, we show that physical proximity does not necessarily instruct transcriptional states. Moreover, multi-way analyses reveal that multiple CRMs spatially coalesce to form hubs. Loops and CRM hubs are established early during development, before the emergence of TADs. Moreover, CRM hubs are formed, in part, via the action of the pioneer transcription factor Zelda and precede transcriptional activation. Our approach provides insight into the role of CRM-promoter interactions in defining transcriptional states, as well as distinct cell types.
细胞命运的获得被认为依赖于远程顺式调控模块（CRMs）的特定相互作用，例如增强子和靶启动子。然而，染色质结构和基因表达之间的确切相互作用仍然不清楚，特别是在多细胞发育生物体内。在本研究中，我们采用 Hi-M，一种单细胞空间基因组学方法，来检测早期果蝇发育过程中拓扑关联域（TAD）内 CRM-启动子环相互作用。通过比较不同细胞类型中的顺式调控环，我们表明物理接近不一定指导转录状态。此外，多向分析表明，多个 CRM 空间上聚集形成枢纽。环和 CRM 枢纽在 TAD 出现之前的早期发育过程中就已经建立。此外，CRM 枢纽的形成部分是通过先驱转录因子 Zelda 的作用实现的，并且先于转录激活。我们的方法提供了对 CRM-启动子相互作用在定义转录状态以及不同细胞类型中的作用的深入了解。
