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

Abstract

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.

Figure 1

Short-, medium- and long-range enhancers may utilize distinct mechanisms to facilitate communication with promoters. For canonical short-range enhancers, a transcription complex consisting of TFs, coactivators, and RNA polymerase II is typically sufficient for target gene activation. At longer ranges (> 50 kb), enhancers increasingly depend on cohesin, architectural proteins, and other looping cofactors.

Figure 2

A cis-regulatory map of a typical distally regulated developmental gene in an active state. Several types of cis-acting regulatory DNA elements control developmental gene expression, most of which are located within the same TAD. Enhancers (light gray) are the primary regulators of gene expression. CTCF sites (light blue) participate in TAD boundary formation, E-P insulation, microcompartment formation, and supporting E-P interactions. Facilitator elements (purple) do not have enhancer activity but support E-P communication. Developmental genes might rely on additional unidentified types of cis-regulatory elements (orange) for full transcriptional activation. A contact matrix showing chromatin interactions is shown in red, where circles and squares depict enhancer and structural CTCF loops, respectively.