Topologically associating domain
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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. These three-dimensional chromosome structures are present in animals as well as some plants, fungi, and bacteria. TADs can range in size from thousands to millions of DNA bases.
The functions of TADs are not fully understood, but in some cases, disrupting TADs leads to disease because changing the 3D organization of the chromosome disrupts gene regulation. 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.
Discovery and definition
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 fruit flies (Drosophila), mouse and human genomes, but not in the wine yeast Saccharomyces cerevisiae.
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". 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.
Mechanisms of formation
A number of proteins are known to be associated with TAD formation including the protein CTCF and the protein complex cohesin. 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.
Computer simulations have shown that chromatin loop extrusion driven by transciption 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. 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. However, proof for DNA loop-extrusion is so far limited to condensin (cohesin's sister protein complex) only.
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.
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.
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.
Relationship with other structural features of the genome
TADs have been reported to be the same as replication domains, regions of the genome that are copied (replicated) at the same time during S phase of cell division. Insulated neighborhoods, DNA loops formed by CTCF/cohesin-bound regions, are proposed to functionally underlie TADs.
Role in disease
For example, genomic structural variants that disrupt TAD boundaries have been reported to cause developmental disorders such as human limb malformations. 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), gliomas, and colorectal cancer.
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. LADs consist mostly of transcriptionally silent chromatin, being enriched with trimethylated Lys27 on histone H3, which is a common posttranslational histone modification of heterochromatin. LADs have CTCF-binding sites at their periphery.
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