Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation

The primary regulators of metazoan gene expression are enhancers, originally functionally defined as DNA sequences that can activate transcription at promoters in an orientation-independent and distance-independent manner. Despite being crucial for gene regulation in animals, what mechanisms underlie enhancer selectivity for promoters, and more fundamentally, how enhancers interact with promoters and activate transcription, remain poorly understood. In this Review, we first discuss current models of enhancer–promoter interactions in space and time and how enhancers affect transcription activation. Next, we discuss different mechanisms that mediate enhancer selectivity, including repression, biochemical compatibility and regulation of 3D genome structure. Through 3D polymer simulations, we illustrate how the ability of 3D genome folding mechanisms to mediate enhancer selectivity strongly varies for different enhancer–promoter interaction mechanisms. Finally, we discuss how recent technical advances may provide new insights into mechanisms of enhancer–promoter interactions and how technical biases in methods such as Hi-C and Micro-C and imaging techniques may affect their interpretation. Gene regulation in animals depends chiefly on enhancers, yet the underlying mechanisms are poorly understood. This Review discusses enhancer–promoter interactions and transcription activation, focusing on how enhancer–promoter selectivity is achieved and on recent technical advances that may provide new insights into transcription activation.