title: 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.
authors.affiliation: Program for Research in Mathematics, Engineering and Science for High School Students, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Undergraduate Research Opportunities Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Boryana
authors.initials: B
authors.lastname: Doyle
authors.affiliation: Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Fudenberg
authors.affiliation: Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Maxim
authors.initials: M
authors.lastname: Imakaev
authors.affiliation: Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, United States of America; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Leonid A
authors.initials: LA
authors.lastname: Mirny
mesh_terms: D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism*; D019295:Computational Biology; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011487:Protein Conformation
chemical_list: D002843:Chromatin