The assembly and functions of multiway enhancer-promoter hubs

Single enhancer-promoter communication, once conceptualized through a simple 'bridge model' of direct molecular contact, is now redefined by the concept of hubs. The term 'hub' is often used interchangeably with other nuclear structures and concepts; however, in this review, we define a hub as a spatial cluster of multiple cis-regulatory elements (CREs), including enhancers and promoters, originating from the same or different chromosomes. These hubs represent dynamic and transient assemblies that coordinate regulatory interactions within the three-dimensional nuclear landscape. A variety of partially overlapping mechanisms, including phase-separation, loop extrusion, protein scaffolding, and actin myosin-driven chromatin mobility, have been proposed to facilitate their formation. However, the organizational principles governing these multi-CREs interacting hubs and their roles in orchestrating gene expression programs remain only partially understood. In this review, we synthesize emerging insights into the formation, function, and regulatory architecture of these transcriptional hubs and propose that they confer robustness, coordination, and flexibility to gene regulation across diverse cellular and developmental contexts.