The interdependence of gene-regulatory elements and the 3D genome

Abstract

Imaging studies, high-resolution chromatin conformation maps, and genome-wide occupancy data of architectural proteins have revealed that genome topology is tightly intertwined with gene expression. Cross-talk between gene-regulatory elements is often organized within insulated neighborhoods, and regulatory cues that induce transcriptional changes can reshape chromatin folding patterns and gene positioning within the nucleus. The cause-consequence relationship of genome architecture and gene expression is intricate, and its molecular mechanisms are under intense investigation. Here, we review the interdependency of transcription and genome organization with emphasis on enhancer-promoter contacts in gene regulation.

Figure 1.

Subnuclear positioning and chromatin loops influence transcriptional activity. Nuclear positioning and gene expression level are related. Repressed chromatin is often found at the periphery, active DNA tends to be located more centrally. Chromosomes occupy distinct CTs, and genes can be extruded from these regions to aggregate with other sites of comparable transcriptional activity. Regulatory elements such as enhancers serve as a binding platforms for transcription factors (TFs), and communication with target genes is allowed for by long-range chromatin contacts (loops). A gene can be activated by multiple enhancers, and movement to specific nuclear sites can cause changes in expression of unrelated nearby genes, a process called bystander activation.

Figure 2.

Interactions between gene-regulatory elements. (A) Schematic of how two promoters can compete for enhancer contact (left panel) or how one enhancer can drive expression of two genes simultaneously (right panel). Hypothetical RNA FISH analysis of transcriptional bursts of both genes (green and red) is indicated in DAPI-stained (blue) nuclei. (B) Birth of a new transcriptional start site as a result of a single-nucleotide polymorphism (SNP) can result in decreased gene expression of the endogenous enhancer target. This phenomenon can underlie reduced α-globin expression in α-thalassemia (De Gobbi et al., 2006). (C) Loss of a transcriptional start site can direct the regulatory influence of an enhancer to one rather than two genes. MYC overexpression as a result of such loss of competition has been implicated in cancer (Cho et al., 2018).

Figure 3.

Different modes of insulator function. Insulators are reduced for regulatory interactions to occur across them. This can be mediated by enhancer–promoter blocking (A), enhancer sequestration by direct contact (B), or isolation of regulatory elements through insulator–insulator interaction (C).