Functional and topological characteristics of mammalian regulatory domains

Abstract

Long-range regulatory interactions play an important role in shaping gene-expression programs. However, the genomic features that organize these activities are still poorly characterized. We conducted a large operational analysis to chart the distribution of gene regulatory activities along the mouse genome, using hundreds of insertions of a regulatory sensor. We found that enhancers distribute their activities along broad regions and not in a gene-centric manner, defining large regulatory domains. Remarkably, these domains correlate strongly with the recently described TADs, which partition the genome into distinct self-interacting blocks. Different features, including specific repeats and CTCF-binding sites, correlate with the transition zones separating regulatory domains, and may help to further organize promiscuously distributed regulatory influences within large domains. These findings support a model of genomic organization where TADs confine regulatory activities to specific but large regulatory domains, contributing to the establishment of specific gene expression profiles.

Spatial Organization of Epigenomes

“…Thus, TADs are thought to spatially compartmentalize the linear genome into regulatory units of chromatin where, for example, genes can be regulated independently from their neighbours. This hypothesis is supported by the observation that gene expression patterns within TADs tend to correlate during differentiation [24], and that the activity of a regulatory sensor inserted at several hundred different sites consistently spans large regions correlating with the size and position of TADs [36].…”

Topologically-associating domains: gene warehouses adapted to serve transcriptional regulation

“…These domains may be defined as areas of the genome where the expression of all or most of the genes present is controlled by the same set of regulatory elements. The recently described regulatory archipelagos 4 and regulatory domains 25 fit well within this definition. They represent large (up to one megabase) segments of the genome containing nonrelated genes that demonstrate a similar tissue-specificity of expression.…”

“…Reporter genes integrated into such a domain under the control of a minimal promoter demonstrate tissue-specific expression profiles typical for the domain as a whole. 25 Notably, current evidence suggests that the tissuespecificity of gene expression is determined by enhancers rather than by promoters. Each tissue-specific gene is likely to be controlled by several enhancers, and, vice versa, one enhancer may influence the expression of more than one gene.…”

“…For this reason, the above described regulatory domains (regulatory archipelagos) generally colocalize with TADs. 25 A restriction of the spatial contacts within a TAD appears to be biologically relevant as the fusion of TADs results in dramatic changes of promoter-enhancer interactions and the deregulation of the involved genes. 29 Notably, current models of eukaryotic genome functional domains do not assume that these domains are continuous on a chromatin fiber.…”

Oncometabolite Tinkers with Genome Folding, Boosting Oncogene Expression

“…Loss of CTCF binding correlates with increased DNA methylation, and preferentially occurs at CTCF binding sites with motifs that contain CG dinucleotides as targets of DNA methylation [2]. DNA methylation may not be the only cause of altered CTCF binding in IDH mutant cells: At some sites at least, the reported increase in DNA methylation is smaller than the observed drop in CTCF binding [2], and increased DNA methylation does not explain the new CTCF binding In normal cells, genes in the same domain show more similar expression than genes located in separate domains, in part because they share access to gene regulatory elements [7]. In this way, spatial segmentation of the genome facilitates the regulation of gene expression.…”