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Concept
Topologically associating domain
Summary
A topologically associating domain (TAD) is a self-interacting genomic region, meaning that DNA sequences within a TAD physically interact with each other more frequently than with sequences outside the TAD. The median size of a TAD in mouse cells is 880 kb, and they have similar sizes in non-mammalian species. Boundaries at both side of these domains are conserved between different mammalian cell types and even across species and are highly enriched with CCCTC-binding factor (CTCF) and cohesin. In addition, some types of genes (such as transfer RNA genes and housekeeping genes) appear near TAD boundaries more often than would be expected by chance.
The functions of TADs are not fully understood and are still a matter of debate. Most of the studies indicate TADs regulate gene expression by limiting the enhancer-promoter interaction to each TAD; however, a recent study uncouples TAD organization and gene expression. Disruption of TAD boundaries are found to be associated with wide range of diseases such as cancer, variety of limb malformations such as synpolydactyly, Cooks syndrome, and F-syndrome, and number of brain disorders like Hypoplastic corpus callosum and Adult-onset demyelinating leukodystrophy.
The mechanisms underlying TAD formation are also complex and not yet fully elucidated, though a number of protein complexes and DNA elements are associated with TAD boundaries. However, the handcuff model and the loop extrusion model describe the TAD formation by the aid of CTCF and cohesin proteins. Furthermore, it has been proposed that the stiffness of TAD boundaries itself could cause the domain insulation and TAD formation.
TADs are defined as regions whose DNA sequences preferentially contact each other. They were discovered in 2012 using chromosome conformation capture techniques including Hi-C. They have been shown to be present in multiple species, including fruit flies (Drosophila), mouse, plants, fungi and human genomes. In bacteria, they are referred to as Chromosomal Interacting Domains (CIDs).
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