Mechanisms and functional implications of long-range enhancer-dependent gene regulation

Metazoan development relies on the coordinated establishment of diverse gene regulatory programs that drive the formation of specific cell types, tissues and organs. The temporal and spatial control of gene expression is achieved through the concerted activity of multiple classes of cis-regulatory elements encoded in the genome. Among these, enhancers enable the establishment of specific and precise gene expression patterns and control gene expression over long linear distances, a property often referred to as distance-independent regulatory activity. However, enhancer activity is, in fact, inversely correlated with linear genomic distance, and target gene expression and transcriptional precision decrease with increasing enhancer-promoter linear distances. Here, we highlight emerging insights into multiple mechanisms that enable enhancers to precisely and robustly activate gene expression across large genomic distances. Finally, we provide a more speculative perspective on the potential advantages that long-range regulation might confer during the establishment of developmental gene expression programs.