Three-dimensional genome architecture and emerging technologies: looping in disease

Abstract

Genome compaction is a universal feature of cells and has emerged as a global regulator of gene expression. Compaction is maintained by a multitude of architectural proteins, long non-coding RNAs (lncRNAs), and regulatory DNA. Each component comprises interlinked regulatory circuits that organize the genome in three-dimensional (3D) space to manage gene expression. In this review, we update the current state of 3D genome catalogues and focus on how recent technological advances in 3D genomics are leading to an enhanced understanding of disease mechanisms. We highlight the use of genome-wide chromatin conformation capture (Hi-C) coupled with oligonucleotide capture technology (capture Hi-C) to map interactions between gene promoters and distal regulatory elements such as enhancers that are enriched for disease variants from genome-wide association studies (GWASs). We discuss how aberrations in architectural units are associated with various pathological outcomes, and explore how recent advances in genome and epigenome editing show great promise for a systematic understanding of complex genetic disorders. Our growing understanding of 3D genome architecture-coupled with the ability to engineer changes in it-may create novel therapeutic opportunities.

Fig. 1

Hierarchical chromatin organization. Top tier: higher-order compartments A and B, where A is an active compartment and B is an inactive or densely packed compartment (beige-colored top-most triangles). Moving downward, topologically associated domains (TADs) are organized into increasingly higher-resolution structures. Second tier: representative metaTAD structure (gray-colored triangle), where many TADs together form one metaTAD. Inter-TAD interactions, while more sparse, can be detected. Third tier: TADs (light pink triangle) consist of numerous intra-TAD regulatory loops (small red triangles in TADs). These regulatory loops are major governing factors for differential transcriptional output. In tiers 1–3, triangles represent higher-frequency contacts of the three-dimensional (3D) genome shown in two dimensions (2D). Tier four illustrates how a TAD may look in 3D, comprising intra-TAD regulatory loops. Representative examples of regulatory loops are also shown: one enhancer to multiple promoter interactions, promoter–promoter interactions, and multiple enhancers to one promoter interactions. TAD boundaries are marked by the CTCF–cohesin complex (green pentagon). Intra-TAD elements likely consist of different transcription factors (light green circles) and long non-coding RNA (dark gray circles)