Abstract
Using Brownian dynamics simulations, we investigate here one of possible roles of supercoiling within topological domains constituting interphase chromosomes of higher eukaryotes. We analysed how supercoiling affects the interaction between enhancers and promoters that are located in the same or in neighbouring topological domains. We show here that enhancer–promoter affinity and supercoiling act synergistically in increasing the fraction of time during which enhancer and promoter stay in contact. This stabilizing effect of supercoiling only acts on enhancers and promoters located in the same topological domain. We propose that the primary role of recently observed supercoiling of topological domains in interphase chromosomes of higher eukaryotes is to assure that enhancers contact almost exclusively their cognate promoters located in the same topological domain and avoid contacts with very similar promoters but located in neighbouring topological domains.
Highlights
Expression of many developmentally regulated genes in higher eukaryotes requires contacts between gene promoters and distal regulatory elements known as enhancers [1,2]
How is this fidelity of enhancer–promoter pairs assured in highly crowded nuclei where most chromatin regions have the potential to interact with each other [6]? This question was partially answered with the demonstration that interphase chromosomes are divided into topological domains with the average size of ∼1 Mb [7,8,9]
We show, using Brownian dynamics simulations that when enhancer and its cognate promoter are placed in the same topological domain there is a synergism between supercoiling and enhancer–promoter affinity
Summary
Expression of many developmentally regulated genes in higher eukaryotes requires contacts between gene promoters and distal (up to 1 Mb apart) regulatory elements known as enhancers [1,2]. Studies of interacting enhancer–promoter pairs showed that there are several ‘complementary’ classes of enhancers and their cognate promoters [4,5]. In healthy cells enhancers find their cognate promoters without forming stable contacts with many other similar promoters to which they have similar affinity. How is this fidelity of enhancer–promoter pairs assured in highly crowded nuclei where most chromatin regions have the potential to interact with each other [6]? We show, using Brownian dynamics simulations that when enhancer and its cognate promoter are placed in the same topological domain there is a synergism between supercoiling and enhancer–promoter affinity. We show regulatory advantages of large genomic separation between enhancers and their cognate promoters
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