In search of the determinants of enhancer-promoter interaction specificity

Abstract

Although it was originally believed that enhancers activate only the nearest promoter, recent global analyses enabled by high-throughput technology suggest that the network of enhancer-promoter interactions is far more complex. The mechanisms that determine the specificity of enhancer-promoter interactions are still poorly understood, but they are thought to include biochemical compatibility, constraints imposed by the three-dimensional architecture of chromosomes, insulator elements, and possibly the effects of local chromatin composition. In this review, we assess the current insights into these determinants, and highlight the functional genomic approaches that will lead the way towards better mechanistic understanding.

Keywords: biochemical compatibility; chromosome architecture; enhancer–promoter interaction; gene regulation.

Figure 1

Distinct mechanisms can drive promoter–enhancer interaction specificity. (A) Biochemical compatibility. Enhancer E2, but not E1, is compatible with the target promoter (P), explaining the selective interaction of E2 with P. (B) Spatial architecture. While E2 and E3 are both biochemically compatible with the promoter, spatial architecture dictates that only E2 interacts with the promoter. (C) Insulation. Although E3 is compatible with the promoter, their interaction is blocked by the insulator (Ins), possibly by alteration of the 3D structure or because the insulator serves as a decoy (not shown; see main text). (D) Chromatin environment. P selectively contacts E1 because the compatibility of E2 with P has been altered by its chromatin environment. This latter mechanism is still speculative.

Figure 2

The frequency at which two loci encounter each other in 3D space, as estimated from 5C data, is inversely proportional to their linear distance along the genome. The average was calculated based on all loci assayed in [18], and separately for each of the three cell-types studied. Since no filter for statistical significance at the level of individual locus–locus pairs was applied, this analysis represents the average trend of all interactions, including nonspecific ones [18]. Note how contact frequencies at distances of 100 kb are only ~2% of those at 2 kb (dotted line), except for in HeLa cells (~10%).