Models behind the mystery of establishing enhancer-promoter interactions

Enhancers and promoters are transcriptional regulatory elements whose facilitated interactions increase gene expression. Enhancer DNA sequences can be located far away from the promoter sequences that they regulate. Currently, the mechanism facilitating the establishment of enhancer-promoter interactions remains unclear. However, mutations causing errors in these interactions have been linked to cancer and disease, further conveying the need to understand the full mechanism. This review discusses multiple models that have been proposed to describe how enhancers go the distance to interact with promoters. Evidence supporting loop formation models is reviewed in addition to more complex hypotheses involving aspects of 3D chromatin organization and phase separation.