Genetic factors mediating long-range enhancer-promoter communication in mammalian development

Enhancers are remotely located noncoding DNA sequences that regulate gene expression in response to developmental, homeostatic, and environmental cues. Canonical short-range enhancers located <50 kb from their cognate promoters function by binding transcription factors, coactivators, and chromatin modifiers. In this review, we discuss recent evidence that medium-range (50-400 kb) and long-range (>400 kb) enhancers rely on additional mechanisms, including cohesin, CCCTC-binding factor, and high-affinity protein-protein interactions. These mechanisms are crucial for establishing the physical proximity and interaction between enhancers and their target promoters over extended genomic distances and ensuring robust gene activation during mammalian development. Future studies will be critical to unravel their prevalence and evolutionary significance across various genomic loci, cell types, and species.