Chromatin Loops as Allosteric Modulators of Enhancer-Promoter Interactions
Author(s)Fudenberg, Geoffrey; Mirny, Leonid A.; Doyle, Boryana G.; Imakaev, Maksim Viktorovich
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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.
DepartmentInstitute for Medical Engineering and Science; Massachusetts Institute of Technology. Department of Physics; Massachusetts Institute of Technology. School of Engineering; Massachusetts Institute of Technology. School of Science
PLoS Computational Biology
Public Library of Science
Doyle, Boryana, Geoffrey Fudenberg, Maxim Imakaev, and Leonid A. Mirny. “Chromatin Loops as Allosteric Modulators of Enhancer-Promoter Interactions.” Edited by Marc A. Marti-Renom. PLoS Comput Biol 10, no. 10 (October 23, 2014): e1003867.
Final published version