Gilad Barshad1,2 and Charles G. Danko1,2 1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA; 2Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA Corresponding authors: dankocgmail.com, barshadtechnion.ac.il

Enhancer–promoter communication is fundamental to gene regulation in metazoans, yet the mechanisms underlying these interactions remain debated. Two primary models have been proposed: the structural bridge model, in which enhancers and promoters come into close proximity through stable, protein-mediated interactions, and the hub model, in which dynamic clusters of transcription-associated proteins facilitate communication over variable distances. Emerging evidence suggests that although enhancer–promoter pairs do come into close proximity during transcriptional activation, these interactions are highly transient, and the precise distances remain challenging to measure. Moving forward, resolving the distinctions between these models will require novel techniques to more precisely measure the spatial and temporal dynamics of enhancer–promoter interactions. Understanding how enhancers interact with promoters will deepen our understanding of the regulation of gene expression and the molecular underpinnings of transcriptional control.