Topologically associating domain

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.[1] The median size of a TAD in mouse cells is 880 kb, and they have similar sizes in non-mammalian species.[2] Boundaries at both side of the these domains are conserved between different mammalian cell types and even across species[2] and are highly enriched with CCCTC-binding factor (CTCF) and cohesin binding sites.[1] 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.[3][4]

Topologically associating domains within chromosome territories, their borders and interactions

The functions of TADs are not fully understood and still is a matter of debate. Most of the studies indicate TADs regulate gene expression by limiting the enhancer-promoter interaction to each TAD,[5] however, a recent study uncouples TAD organization and gene expression.[6] Disruption of TAD boundaries are found to be associated with wide range of diseases such as cancer,[7][8][9] variety of limb malformations such as synpolydactyly, Cooks syndrome, and F-syndrome,[10] and number of brain disorders like Hypoplastic corpus callosum and Adult-onset demyelinating leukodystrophy.[10]

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 are described to describe the TAD formation by the aid of CTCF and cohesin proteins.[11] Furthermore, it has been proposed that the stiffness of TAD boundaries itself could cause the domain insulation and TAD formation.[11]

Discovery and diversity

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.[3][12][4] They have been shown to be present in multiple species,[13] including fruit flies (Drosophila),[14] mouse,[3] plants, fungi and human[4] genomes. In bacteria, they are referred to as Chromosomal Interacting Domains (CIDs).[13]

Analytical tools and databases

TAD locations are defined by applying an algorithm to Hi-C data. For example, TADs are often called according to the so-called "directionality index".[4] The directionality index is calculated for individual 40kb bins, by collecting the reads that fall in the bin, and observing whether their paired reads map upstream or downstream of the bin (read pairs are required to span no more than 2Mb). A positive value indicates that more read pairs lie downstream than upstream, and a negative value indicates the reverse. Mathematically, the directionality index is a signed chi-square statistic.

The development of 3D genome browsers and databases such as The 3D Genome Browser,[15] 3DIV,[16] 3D-GNOME[17], and TADKB[18] have enabled us to visualize the TAD organization of regions of interest in different cell types.

Mechanisms of formation
DNA loop extrusion through cohesin rings

A number of proteins are known to be associated with TAD formation including the protein CTCF and the protein complex cohesin.[1] It is also unknown what components are required at TAD boundaries; however, in mammalian cells, it has been shown that these boundary regions have comparatively high levels of CTCF binding. 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.[3][4]

Computer simulations have shown that chromatin loop extrusion driven by transcription generated supercoiling ensures that cohesin relocalizes quickly and loops grow with reasonable speed and in a good direction. In addition, the supercoiling-driven loop extrusion mechanism is consistent with earlier explanations proposing why TADs flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites. In this model, the supercoiling also stimulates enhancer promoter contacts and it is proposed that transcription of eRNA sends the first wave of supercoiling that can activate mRNA transcription in a given TAD.[19][20] Computational models also showed that cohesin rings act like a very efficient molecular comb, pushing knots and entanglements such as in catenanes towards border of TADs where these are removed by the action of topoisomerases. Consistently, removal of entanglements during loop extrusion also increases degree of segregation between chromosomes.[21] However, proof for DNA loop-extrusion is so far limited to condensin (cohesin's sister protein complex) only.[22]

Properties

Conservation

TADs have been reported to be relatively constant between different cell types (in stem cells and blood cells, for example), and even between species in specific cases.[23][24]

Relationship with promoter-enhancer contacts

The majority of observed interactions between promoters and enhancers do not cross TAD boundaries. Removing a TAD boundary (for example, using CRISPR to delete the relevant region of the genome) can allow new promoter-enhancer contacts to form. This can affect gene expression nearby - such misregulation has been shown to cause limb malformations (e.g. polydactyly) in humans and mice.[23]

Computer simulations have shown that transcription-induced supercoiling of chromatin fibres can explain how TADs are formed and how they can assure very efficient interactions between enhancers and their cognate promoters located in the same TAD.[20]

Relationship with other structural features of the genome

Replication timing domains have been shown to be associated with TADs as their boundary is co localized with the boundaries of TADs that are located at either sides of compartments.[25] Insulated neighborhoods, DNA loops formed by CTCF/cohesin-bound regions, are proposed to functionally underlie TADs.[26]

Role in disease

Disruption of TAD boundaries can affect the expression of nearby genes, and this can cause disease.[27]

For example, genomic structural variants that disrupt TAD boundaries have been reported to cause developmental disorders such as human limb malformations.[28][29][30] Additionally, several studies have provided evidence that the disruption or rearrangement of TAD boundaries can provide growth advantages to certain cancers, such as T-cell acute lymphoblastic leukemia (T-ALL),[31] gliomas,[32] and lung cancer.[33]

Lamina-associated domains
LADs (dark gray lines) and proteins that interact with them. Lamina is indicated by green curve.
Main article: Nuclear lamina

Lamina-associated domains (LADs) are parts of the chromatin that heavily interact with the lamina, a network-like structure at the inner membrane of the nucleus.[34] LADs consist mostly of transcriptionally silent chromatin, being enriched with trimethylated Lys27 on histone H3, which is a common posttranslational histone modification of heterochromatin.[35] LADs have CTCF-binding sites at their periphery.[34]

See also

References
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