Molecular architecture of enhancer–promoter interaction

Temporal and spatial specificity of gene expression is highly regulated through a rich milieu of regulatory DNAs embedded in the genome. Enhancers represent a major class of regulatory DNAs that consist of a cluster of binding sites for sequence-specific transcription factors and are thought to facilitate recruitment of transcription machinery to their target promoters from remote locations. It has been over four decades since the discovery of prototypic simian virus 40 enhancer, yet the nature of enhancer-promoter interaction still remains an outstanding mystery in gene regulation. The aim of this review is to comprehensively overview molecular mechanisms underlying enhancer-promoter interaction including the roles of looping factors, higher-order genome topology, and dynamic clustering of transcription apparatus within a nucleus. We propose that cooperative interplay between 'looping' and 'hub' permits distal enhancers to specifically and dynamically modulate target gene expression over large distances.