Chromatin Loops as Allosteric Modulators of Enhancer-Promoter Interactions

Abstract

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 SummaryIn 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 All rights reserved. No reuse allowed without permission.

Dynamics of chromatin accessibility and epigenetic state in response to UV damage

“…These contradicting associations of expression and H3K27ac might be due to a limitation in assigning enhancers to their target genes. This goes along with previous suggestions that enhancer-nearest gene pairing only holds true for ∼40% of genes (Andersson et al, 2014;Doyle et al, 2014;Samee and Sinha, 2014). However, as such contradictory findings were also observed when correlating H3K27ac enrichment changes at promoters to gene expression changes, it is likely that other chromatin features and regulatory mechanisms might be more important in determining the transcriptional state of these genes that we are unable to capture here or that the expression status of these genes is influenced by post-transcriptional mechanisms.…”

Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains

“…3B) apparently contradicts our model, suggesting that additional ways of chromatin self-organization could exist. One possibility is the establishment of long-range contacts between enhancers and their cognate promoters, as well as loops between pairs of insulators (Doyle et al 2014). Such loops formed inside active unstructured chromatin linkers (i.e., inter-TADs) could probably be sufficient to compact them and thus to fold into TADs.…”

“…However, domains of similar sizes but without a loop were observed as well (so-called "ordinary domains") (Rao et al 2014). Thirdly, polymer simulations of a permanent chromatin loop yield a noticeable interaction between the loop bases on a simulated Hi-C map but without the characteristic square shape of a TAD (Doyle et al 2014). Loops of this kind are thought to occur between insulator proteins such as Su(Hw) in the "topological insulation" model (Gohl et al 2011).…”

Dynamics and function of distal regulatory elements during neurogenesis and neuroplasticity

“…S2Q). The genes that do not exhibit induced behavior in association with such distal elements may be wrongly assigned due to computational limitations and that the enhancernearest TSS pairing only holds for up to 40% of enhancers (Andersson et al 2014;Doyle et al 2014;Samee and Sinha 2014). The correlation of unique distal H3K27ac-accessible sites with nearest gene expression was much higher in TND1 and TND10 than in NPs, further suggesting that distal gene regulation becomes more defined as cells reach a terminally differentiated state.…”