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PLoS Comput Biol. 2014 Oct 23;10(10):e1003867. doi: 10.1371/journal.pcbi.1003867. eCollection 2014 Oct.

Chromatin loops as allosteric modulators of enhancer-promoter interactions.

Author information

1
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.
2
Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, United States of America.
3
Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
4
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.

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.

PMID:
25340767
PMCID:
PMC4207457
DOI:
10.1371/journal.pcbi.1003867
[Indexed for MEDLINE]
Free PMC Article

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