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

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.