When TADs go bad: chromatin structure and nuclear organisation in human disease

Abstract

Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease.

Keywords: TADs; chromatin organisation; developmental disorders.

Figure 1.. Schematic diagram of regulatory re-wiring following the deletion of a domain boundary.

( A) Interactions between enhancers and their target genes occur within chromatin domains. The deletion of a boundary region leads to novel gene-enhancer interactions between previously insulated elements; this process may lead to the spatial or temporal mis-expression of genes. ( B) The same scenario as in ( A) is drawn as represented by a high-throughput chromosome conformation capture (Hi-C) interaction map. Red triangles: topologically associating domains; yellow boxes: regulatory elements; blue boxes: target genes; green circles: insulator elements. Further examples of pathogenic genomic rearrangements, including insulator-spanning tandem duplications, are illustrated in .