A Looping-Based Model for Quenching Repression

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 Summary: Biological 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.