topologically associating domain

We usually picture the genome as a line of letters, but inside a nucleus it is folded into a three-dimensional shape, and that shape is not random. Imagine a long garden hose looped into a series of self-contained coils: stretches within one coil bump into each other constantly, while stretches in different coils rarely touch. The genome's coils are called topologically associating domains, or TADs.

A TAD is a region of a chromosome whose DNA sequences contact one another far more often than they contact sequences in neighbouring regions — a self-interacting neighbourhood, typically hundreds of thousands to about a million base pairs across. They are detected by methods that capture which bits of DNA are physically close (chromosome conformation capture, such as Hi-C), which produce maps showing square blocks of high contact along the genome. TADs are thought to form largely by loop extrusion: ring-shaped cohesin proteins reel DNA through themselves to grow a loop until they hit boundary sites bound by the protein CTCF, which act like stoppers marking the edges of each domain.

TADs matter because they organize gene regulation in space. Enhancers tend to act on genes within the same TAD and are insulated from genes in the next one, so the boundaries effectively wire each enhancer to its proper targets. When a boundary is deleted or scrambled, an enhancer can spill over and switch on a gene it should never touch — a 'rewiring' that can cause developmental disorders and has been linked to some cancers. The study of TADs is part of the young, fast-moving field of three-dimensional genome organization, and it shows that where DNA sits in space is itself a layer of information.