Chromatin Loops as Allosteric Modulators of Enhancer-Promoter Interactions

The classic model of eukaryotic gene expression requires direct spatial contact between a distal enhancer and a proximal promoter. Recent Chromosome Conformation Capture (3C) studies show that enhancers and promoters are embedded in a complex network of looping interactions. Here we use a polymer model of chromatin fiber to investigate whether, and to what extent, looping interactions between elements in the vicinity of an enhancer-promoter pair can influence their contact frequency. Our equilibrium polymer simulations show that a chromatin loop, formed by elements flanking either an enhancer or a promoter, suppresses enhancer-promoter interactions, working as an insulator. A loop formed by elements located in the region between an enhancer and a promoter, on the contrary, facilitates their interactions. We find that different mechanisms underlie insulation and facilitation; insulation occurs due to steric exclusion by the loop, and is a global effect, while facilitation occurs due to an effective shortening of the enhancer-promoter genomic distance, and is a local effect. Consistently, we find that these effects manifest quite differently for in silico 3C and microscopy. Our results show that looping interactions that do not directly involve an enhancer-promoter pair can nevertheless significantly modulate their interactions. This phenomenon is analogous to allosteric regulation in proteins, where a conformational change triggered by binding of a regulatory molecule to one site affects the state of another site.Author Summary: In eukaryotes, enhancers directly contact promoters over large genomic distances to regulate gene expression. Characterizing the principles underlying these long-range enhancer-promoter contacts is crucial for a full understanding of gene expression. Recent experimental mapping of chromosomal interactions by the Hi-C method shows an intricate network of local looping interactions surrounding enhancers and promoters. We model a region of chromatin fiber as a long polymer and study how the formation of loops between certain regulatory elements can insulate or facilitate enhancer-promoter interactions. We find 2–5 fold insulation or facilitation, depending on the location of looping elements relative to an enhancer-promoter pair. These effects originate from the polymer nature of chromatin, without requiring additional mechanisms beyond the formation of a chromatin loop. Our findings suggest that loop-mediated gene regulation by elements in the vicinity of an enhancer-promoter pair can be understood as an allosteric effect. This highlights the complex effects that local chromatin organization can have on gene regulation.