Topologically associating domain

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A topologically associating domain (TAD) is a self-interacting genomic region. H. DNA sequences within a TAD interact physically more frequently with one another than with sequences outside the TAD. These three-dimensional chromosome structures are present in animals as well as in some plants, fungi and bacteria. TADs can vary in size from thousands to millions of DNA bases.

Topologically associated domains within chromosome territories. Their limits and interactions are shown.

The functions of TADs are not fully understood, but in some cases, the disruption of TADs leads to disease, as the change in the 3D organization of the chromosome disrupts gene regulation. The mechanisms of TAD formation are also complex and not fully understood, although a number of protein complexes and DNA elements are associated with TAD boundaries.

Discovery and definition

TADs are defined as regions whose DNA sequences are preferably in contact with one another. They were discovered in 2012 using the Chromosome Conformation Capture technique including Hi-C. The further developments of these technologies, 4C and Hi-C, enabled the genome-wide determination of all interacting gene loci . TADs have been shown to be present in fruit flies ( Drosophila ), mice, and human genomes, but not in the yeast Saccharomyces cerevisiae .

TADs have the property that chromosomal interactions take place with a high frequency within the domains. The interactions between the TADs are only weak among themselves.

The positions of TADs are defined by applying an algorithm to Hi-C data. For example, TADs are often determined by the so-called "Directionality Index". This directional index is calculated for individual 40 kb sections by collecting the sequencing that falls within these sections. It is then observed whether their paired sequences are before or after the section (these pairings are required in order not to span more than 2Mb). A positive value indicates that there are more pairs of reads downstream than upstream, and a negative value indicates the opposite. Mathematically, the direction index is a signed chi-square statistic .

Mechanisms of origin

Cohesin creates a DNA loop.
Cohesin creates a DNA loop.

A number of proteins are known to be associated with TAD formation, including the protein CTCF and the protein complex cohesin . It is not known which components are needed at the TAD boundaries; however, it has been shown in mammalian cells that these border regions have a comparatively high level of CTCF binding. In addition, some types of genes (such as transfer RNA genes and household genes ) appear near TAD boundaries more often than chance would expect.

All TADs can be recognized on Hi-C contact cards as "triangles", which describe the regions with increased frequency of internal contacts. The triangles formed have very strong peaks in about 50% of the cases. TADs with such contact patterns form chromatin loops with their edge elements touching one another. ChIP-Seq studies showed that touching chromatin regions at the base of the loops formed are bound by CTCF proteins and cohesin.

The loop starts when a cohesin complex attaches to the DNA. Cohesin consists of two connected, ring-shaped sub-units, similar to handcuffs. The DNA enters through one ring and exits through the other. The rings slide along the DNA in the opposite direction. As a result, an ever-growing DNA loop is formed. Only when a ring meets a CTCF molecule that is bound to the DNA can this process be stopped. To do this, the binding sequence for CTCF must point towards the inside of the DNA loop. Otherwise the cohesin ring will slide over it and the loop will continue to grow. The loop formation is complete when both rings of the Cohesin complex have reached an inward CTCF sequence.

Recent models suggest that TADs exist in a supercoiled - ( supercoiled ) DNA structure and that this increases the contacts within a TAD. With the help of molecular dynamic simulations, Racko et al. It was shown that the cohesin complex is pushed further towards the TAD boundaries by supercoiling the DNA, which is produced during transcription. These models also explain what the driving force behind loop formation can be and how to ensure that loops grow quickly and in the right direction.

Furthermore, the loop formation mechanism controlled by supercoiling is in line with previous explanations suggesting why TADs flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites.

properties

Preservation

It has been reported that TADs are relatively constant between different cell types (e.g. in stem cells and blood cells) and in individual cases even between species.

Relationship with promoter-enhancer contacts

The majority of the observed interactions between promoters and enhancers does not exceed the TAD boundaries. Removing a TAD boundary (e.g., using CRISPR to delete the relevant region of the genome) may allow new contacts to be made between promoter and enhancer. This can affect gene expression in the vicinity - such malfunction has been shown to cause limb malformations (e.g., polydactyly ) in humans and mice.

Computer simulations have shown that transcription-induced supercoiling of chromatin fibers can explain how TADs are formed and how they can ensure very efficient interactions between enhancers and their related promoters in the same TAD.

Relationship with other structural features of the genome

It has been reported that topologically associated domains are the same as replication domains. These are regions of the genome that are copied (replicated) at the same time during the S phase of cell division. Isolated neighborhoods, DNA loops formed from CTCF / cohesin-bound regions, should functionally form the basis of the TADs.

Diseases

Disruption of the TAD boundaries can affect the expression of neighboring genes, which can lead to disease.

For example, genomic structural variants that break the TAD boundaries have been reported as the cause of developmental disorders such as malformations of human limbs. In addition, several studies have shown that breaking or rearranging the TAD boundaries can provide growth benefits for certain cancers such as T-cell acute lymphoblastic leukemia (T-ALL), gliomas, and colon cancer.

Lamina-associated domains

LADs (dark gray lines) and proteins that interact with them. Lamina is indicated by a green curve.

Lamina-associated domains (LADs) are parts of chromatin that interact strongly with the lamina , a network-like structure on the inner membrane of the nucleus. LADs consist primarily of transcriptionally silent chromatin enriched with trimethylated Lys27 on histone H3, which is a common post-translational histone modification of heterochromatin . LADs have CTCF binding sites on their periphery.

Individual evidence

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  2. ^ A b Elphège P. Nora, Bryan R. Lajoie, Edda G. Schulz, Luca Giorgetti, Ikuhiro Okamoto: Spatial partitioning of the regulatory landscape of the X-inactivation center . In: Nature . tape 485 , no. 7398 , May 2012, ISSN  0028-0836 , p. 381–385 , doi : 10.1038 / nature11049 , PMID 22495304 , PMC 3555144 (free full text).
  3. ^ Wouter de Laat, Denis Duboule: Topology of mammalian developmental enhancers and their regulatory landscapes . In: Nature . tape 502 , no. 7472 , October 2013, ISSN  0028-0836 , p. 499–506 , doi : 10.1038 / nature12753 ( nature.com [accessed July 16, 2019]).
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  5. ↑ Jesse R. Dixon, Siddarth Selvaraj, Feng Yue, Audrey Kim, Yan Li: Topological domains in mammalian genomes identified by analysis of chromatin interactions . In: Nature . tape 485 , no. 7398 , May 2012, ISSN  0028-0836 , p. 376-380 , doi : 10.1038 / nature11082 , PMID 22495300 , PMC 3356448 (free full text).
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