Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during early Drosophila development
Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during early Drosophila development
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DOI：
10.1038/s41588-021-00816-z
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发表时间：
2021-04-01
期刊：
影响因子：
30.8
通讯作者：
Nollmann, Marcelo
中科院分区：
文献类型：
--
作者：
Espinola, Sergio Martin;Gotz, Markus;Nollmann, Marcelo
使用Hi-M对果蝇发育进行的单细胞分析表明，调节区域之间的物理接近并不一定指导转录状态。多途径分析确定了在拓扑关联域之前出现的监管中心的存在。细胞命运的获得被认为依赖于远程顺式调控模块（crm）的特定相互作用，例如增强子和目标启动子。然而，染色质结构和基因表达之间的确切相互作用仍不清楚，特别是在多细胞发育生物中。在本研究中，我们采用单细胞空间基因组学方法Hi-M来检测果蝇早期发育过程中拓扑相关域（TADs）内的cr -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，我们发现物理接近并不一定指导转录状态。此外，多途径分析表明，多个crm在空间上相互融合形成枢纽。在TADs出现之前，在开发早期就建立了循环和CRM中心。此外，CRM中心的形成部分是通过先驱转录因子Zelda的作用和转录激活之前形成的。我们的方法提供了洞察crm启动子相互作用在定义转录状态中的作用，以及不同的细胞类型。
Single-cell analysis of Drosophila development with Hi-M suggests that physical proximity between regulatory regions does not necessarily instruct transcriptional states. Multi-way analyses identify the existence of regulatory hubs that emerge before topologically associating domains.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.