3D enhancer-promoter interactions and multi-connected hubs: Organizational principles and functional roles

Abstract

The spatiotemporal control of gene expression is dependent on the activity of cis-acting regulatory sequences, called enhancers, which regulate target genes over variable genomic distances and, often, by skipping intermediate promoters, suggesting mechanisms that control enhancer-promoter communication. Recent genomics and imaging technologies have revealed highly complex enhancer-promoter interaction networks, whereas advanced functional studies have started interrogating the forces behind the physical and functional communication among multiple enhancers and promoters. In this review, we first summarize our current understanding of the factors involved in enhancer-promoter communication, with a particular focus on recent papers that have revealed new layers of complexities to old questions. In the second part of the review, we focus on a subset of highly connected enhancer-promoter "hubs" and discuss their potential functions in signal integration and gene regulation, as well as the putative factors that might determine their dynamics and assembly.

Keywords: CP: Molecular biology.

Figure 1.. Factors that mediate enhancer promoter communication

Schematic diagram of different factors involved in enhancer-promoter communication. A) Cohesin loop-extrusion allows distant enhancers and promoters to come into contact with one another. In the cartoon, the Cohesin ring complex is anchored at the promoter. B) Mediator Complex (Med) acts a dynamic, functional bridge between transcription factors (TF) and RNA Pol II to initiate polymerase elongation. C) Low-affinity interactions between TFs, transcriptional co-activators, and other proteins, can form heterogenous condensates that promote and stabilize enhancer-promoter contacts. D) Dimerization (shown) or oligomerization of TFs can physically bridge enhancers and promoters.

Figure 2.. Types of multi-connected hubs

Different types of multi-connected enhancer-promoter hubs. A) Simple promoter hubs involve a single promoter regulated by multiple enhancers. B) Enhancer hubs involve a single enhancer connected to multiple promoters, which may facilitate gene coregulation. C) The most highly-connected hubs often involve multiple promoters and multiple enhancers cross-connected to one another in complex, nested interaction networks.

Figure 3.. Different modes of enhancer regulation in 3D-hubs

Schematic diagram of the different ways multi-connected enhancers and promoters can regulate gene expression. A) Multiple enhancers can work additively or synergistically on a single promoter to increase its activity. B) “Shadow” enhancers appear redundant upon deletion but are thought to promote stable gene expression and developmental robustness. One model for shadow enhancer behavior is that multiple, strong enhancers compete with one another to interact with a single promoter^,. C) A single enhancer can act on multiple connected promoters (blue and magenta) to direct coordinated expression changes in different developmental stages or tissues. Expression of nearby but not-connected promoters (yellow) might follow different regulatory logic.