A looping-based model for quenching repression

Abstract

We model the regulatory role of proteins bound to looped DNA using a simulation in which dsDNA is represented as a self-avoiding chain, and proteins as spherical protrusions. We simulate long self-avoiding chains using a sequential importance sampling Monte-Carlo algorithm, and compute the probabilities for chain looping with and without a protrusion. We find that a protrusion near one of the chain's termini reduces the probability of looping, even for chains much longer than the protrusion-chain-terminus distance. This effect increases with protrusion size, and decreases with protrusion-terminus distance. The reduced probability of looping can be explained via an eclipse-like model, which provides a novel inhibitory mechanism. We test the eclipse model on two possible transcription-factor occupancy states of the D. melanogaster eve 3/7 enhancer, and show that it provides a possible explanation for the experimentally-observed eve stripe 3 and 7 expression patterns. Author SummaryBiological regulation-at-a-distance, whereby a transcription factor (TF) is able to generate susbstantial regulatory effects on gene expression even though it may be bound a large distance away from its target (500 bp-1 Mbp), is only partially understood. Using a biophysical model and a computer simulation that take dsDNA and TF volumes into account, we identify a downregulatory mechanism which functions at large distances, whereby a TF bound within * 150 bp from an activator decreases the probability of looping-based interaction between the activator and the distant core promoter. This "eclipse" mechanism provides insight into the question of how enhancer architecture dictates gene expression.

Positive and Negative Control of Enhancer-Promoter Interactions by Other DNA Loops Generates Specificity and Tunability

“…Single-molecule experiments (Priest et al, 2014a) and chromatin modeling (Doyle et al, 2014) with naked, relaxed DNA suggest that some insulation results from the DNA of the loop shielding the internal site. This mechanism is akin to the proposed ''eclipse'' effect of an obstructing protein bound near the enhancer or the promoter (Pollak et al, 2017). However, only about 2-fold insulation was seen (Doyle et al, 2014;Priest et al, 2014a), substantially less than we saw in vivo.…”