Enhancer-Promoter Communication: It’s Not Just About Contact

Cis-regulatory elements such as enhancers can be located even a million base pairs away from their cognate promoter and yet modulate gene transcription. Indeed, the 3D organisation of chromatin enables the establishment of long-range enhancer-promoter communication. The observation of long-range enhancer-promoter chromatin loops at active genes originally led to a model in which enhancers and promoters form physical contacts between each other to control transcription. Yet, recent microscopy data has challenged this prevailing activity-by-contact model of enhancer-promoter communication in transcriptional activation. Live single-cell imaging approaches do not systematically reveal a correlation between enhancer-proximity and transcriptional activation. We therefore discuss the need to move from a static to a dynamic view of enhancer-promoter relationships. We highlight recent studies that not only reveal considerable chromatin movement in specific cell types, but suggest links between chromatin compaction, chromatin movement and transcription. We describe the interplay between enhancer-promoter proximity within the context of biomolecular condensates and the need to understand how condensate microenvironments influence the chromatin binding kinetics of proteins that bind at cis-regulatory elements to activate transcription. Finally, given the complex multi-scale interplay between regulatory proteins, enhancer-promoter proximity and movement, we propose the need to integrate information from complementary single-cell next-generation sequencing and live-cell imaging approaches to derive unified 3D theoretical models of enhancer-promoter communication that are ultimately predictive of transcriptional output and cell fate. In time, improved models will shed light on how tissues grow and diseases emerge.