Abstract
Mammalian genomes are partitioned into sub-megabase to megabase-sized units of preferential interactions called topologically associating domains or TADs, which are likely important for the proper implementation of gene regulatory processes. These domains provide structural scaffolds for distant cis regulatory elements to interact with their target genes within the three-dimensional nuclear space and architectural proteins such as CTCF as well as the cohesin complex participate in the formation of the boundaries between them. However, the importance of the genomic context in providing a given DNA sequence the capacity to act as a boundary element remains to be fully investigated. To address this question, we randomly relocated a topological boundary functionally associated with the mouse HoxD gene cluster and show that it can indeed act similarly outside its initial genomic context. In particular, the relocated DNA segment recruited the required architectural proteins and induced a significant depletion of contacts between genomic regions located across the integration site. The host chromatin landscape was re-organized, with the splitting of the TAD wherein the boundary had integrated. These results provide evidence that topological boundaries can function independently of their site of origin, under physiological conditions during mouse development.
Highlights
Inside the cell nucleus, mammalian genomes are organized at various levels or resolution, from the nucleosomal scale to chromosome territories [1]
This complex process is made possible by the folding of chromatin into domains, which are separated from one another by specific genomic regions referred to as boundaries
We report the ability of this region to be accessed by both CTCF and the cohesin complex, and show that this boundary was able to split the 1.2 Mb-large host topologically associating domains (TADs) into two sub-structures
Summary
Mammalian genomes are organized at various levels or resolution, from the nucleosomal scale to chromosome territories [1]. The use of whole-genome chromosome conformation capture techniques (such as Hi-C) in interphase cells identified sub-megabase to megabase (Mb) structures referred to as topologically associating domains (TADs) These domains appear as discrete on-diagonal pyramid shapes in Hi-C maps, reflecting a high frequency of internal interactions, which seemingly participate in enhancer-promoter communication [2,3]. The depletion of these proteins or some of their co-factors alters the formation of loops and TADs genome-wide, it seems to have only minor effects on gene expression [9,10,11,12,13,14], raising questions regarding the impact of chromatin structure upon genome function [15]. It was proposed that chromosome topology may refine the action and timing of distant enhancers on their target genes during development [16,17,18], implying that the importance of such structures should be considered on a case-by-case basis, rather than drawing too global conclusions
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