Chromatin loops as allosteric modulators of enhancer-promoter interactions.

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 mo...

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Autores principales:	Boryana Doyle, Geoffrey Fudenberg, Maxim Imakaev, Leonid A Mirny
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8d1427eb59f74f52ac8f9ea6a2aaf2a3
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spelling	oai:doaj.org-article:8d1427eb59f74f52ac8f9ea6a2aaf2a32021-11-25T05:40:39ZChromatin loops as allosteric modulators of enhancer-promoter interactions.1553-734X1553-735810.1371/journal.pcbi.1003867https://doaj.org/article/8d1427eb59f74f52ac8f9ea6a2aaf2a32014-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1003867https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The 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.Boryana DoyleGeoffrey FudenbergMaxim ImakaevLeonid A MirnyPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 10, p e1003867 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Boryana Doyle Geoffrey Fudenberg Maxim Imakaev Leonid A Mirny Chromatin loops as allosteric modulators of enhancer-promoter interactions.
description	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.
format	article
author	Boryana Doyle Geoffrey Fudenberg Maxim Imakaev Leonid A Mirny
author_facet	Boryana Doyle Geoffrey Fudenberg Maxim Imakaev Leonid A Mirny
author_sort	Boryana Doyle
title	Chromatin loops as allosteric modulators of enhancer-promoter interactions.
title_short	Chromatin loops as allosteric modulators of enhancer-promoter interactions.
title_full	Chromatin loops as allosteric modulators of enhancer-promoter interactions.
title_fullStr	Chromatin loops as allosteric modulators of enhancer-promoter interactions.
title_full_unstemmed	Chromatin loops as allosteric modulators of enhancer-promoter interactions.
title_sort	chromatin loops as allosteric modulators of enhancer-promoter interactions.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/8d1427eb59f74f52ac8f9ea6a2aaf2a3
work_keys_str_mv	AT boryanadoyle chromatinloopsasallostericmodulatorsofenhancerpromoterinteractions AT geoffreyfudenberg chromatinloopsasallostericmodulatorsofenhancerpromoterinteractions AT maximimakaev chromatinloopsasallostericmodulatorsofenhancerpromoterinteractions AT leonidamirny chromatinloopsasallostericmodulatorsofenhancerpromoterinteractions
_version_	1718414529218478080

Chromatin loops as allosteric modulators of enhancer-promoter interactions.

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