Topologically associating domain: Difference between revisions

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A '''topologically associating domain''' (TAD) is a self-interacting genomic region, meaning that [[DNA sequence]]s within a TAD physically interact with each other more frequently than with sequences outside the TAD.<ref name="Pombo20152">{{cite journal | vauthors = Pombo A, Dillon N | title = Three-dimensional genome architecture: players and mechanisms | journal = Nature Reviews. Molecular Cell Biology | volume = 16 | issue = 4 | pages = 245–257 | date = April 2015 | pmid = 25757416 | doi = 10.1038/nrm3965 | s2cid = 6713103 }}</ref> The median size of a TAD in mouse cells is 880 [[Base pair#Length measurements|kb]], and they have similar sizes in non-mammalian species.<ref name=":0">{{cite journal | vauthors = Yu M, Ren B | title = The Three-Dimensional Organization of Mammalian Genomes | journal = Annual Review of Cell and Developmental Biology | volume = 33 | pages = 265–289 | date = October 2017 | pmid = 28783961 | pmc = 5837811 | doi = 10.1146/annurev-cellbio-100616-060531 }}</ref> Boundaries at both side of these domains are conserved between different mammalian cell types and even across species<ref name=":0" /> and are highly enriched with [[CTCF|CCCTC-binding factor (CTCF)]] and [[cohesin]].<ref name="Pombo20152" /> 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.<ref name="Nora201222">{{cite journal | vauthors = Nora EP, Lajoie BR, Schulz EG, Giorgetti L, Okamoto I, Servant N, Piolot T, van Berkum NL, Meisig J, Sedat J, Gribnau J, Barillot E, Blüthgen N, Dekker J, Heard E | display-authors = 6 | title = Spatial partitioning of the regulatory landscape of the X-inactivation centre | journal = Nature | volume = 485 | issue = 7398 | pages = 381–385 | date = April 2012 | pmid = 22495304 | pmc = 3555144 | doi = 10.1038/nature11049 | bibcode = 2012Natur.485..381N }}</ref><ref name="Dixon201222">{{cite journal | vauthors = Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, Hu M, Liu JS, Ren B | display-authors = 6 | title = Topological domains in mammalian genomes identified by analysis of chromatin interactions | journal = Nature | volume = 485 | issue = 7398 | pages = 376–380 | date = April 2012 | pmid = 22495300 | pmc = 3356448 | doi = 10.1038/nature11082 | bibcode = 2012Natur.485..376D }}</ref>
 
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 (genetics)|enhancer]]-[[Promoter (genetics)|promoter]] interaction to each TAD;<ref>{{cite journal | vauthors = Krijger PH, de Laat W | title = Regulation of disease-associated gene expression in the 3D genome | journal = Nature Reviews. Molecular Cell Biology | volume = 17 | issue = 12 | pages = 771–782 | date = December 2016 | pmid = 27826147 | doi = 10.1038/nrm.2016.138 | s2cid = 11484886 }}</ref> however, a recent study uncouples TAD organization and gene expression.<ref>{{cite journal | author1 = Ghavi-Helm Y| author2 = Jankowski A, | author3 = Meiers S| author4 = Viales RR| author5 = Korbel JO| author-link5 =Jan O. Korbel | author6 = Furlong EE | author-link6 =Eileen Furlong| title = Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression | journal = Nature Genetics | volume = 51 | issue = 8 | pages = 1272–1282 | date = August 2019 | pmid = 31308546 | pmc = 7116017 | doi = 10.1038/s41588-019-0462-3 }}</ref> Disruption of TAD boundaries are found to be associated with wide range of diseases such as [[cancer]],<ref>{{cite journal | vauthors = Corces MR, Corces VG | title = The three-dimensional cancer genome | journal = Current Opinion in Genetics & Development | volume = 36 | pages = 1–7 | date = February 2016 | pmid = 26855137 | pmc = 4880523 | doi = 10.1016/j.gde.2016.01.002 }}</ref><ref>{{cite journal | vauthors = Valton AL, Dekker J | title = TAD disruption as oncogenic driver | journal = Current Opinion in Genetics & Development | volume = 36 | pages = 34–40 | date = February 2016 | pmid = 27111891 | pmc = 4880504 | doi = 10.1016/j.gde.2016.03.008 }}</ref><ref>{{cite journal | vauthors = Achinger-Kawecka J, Clark SJ | title = Disruption of the 3D cancer genome blueprint | journal = Epigenomics | volume = 9 | issue = 1 | pages = 47–55 | date = January 2017 | pmid = 27936932 | doi = 10.2217/epi-2016-0111 | doi-access = free }}</ref> variety of limb malformations such as [[synpolydactyly]], [[Cooks syndrome]], and F-syndrome,<ref name=":1">{{cite journal | vauthors = Spielmann M, Lupiáñez DG, Mundlos S | title = Structural variation in the 3D genome | journal = Nature Reviews. Genetics | volume = 19 | issue = 7 | pages = 453–467 | date = July 2018 | pmid = 29692413 | doi = 10.1038/s41576-018-0007-0 | hdl-access = free | s2cid = 22325904 | hdl = 21.11116/0000-0003-610A-5 }}</ref> and number of brain disorders like Hypoplastic corpus callosum and Adult-onset demyelinating leukodystrophy.<ref name=":1" />
 
The mechanisms underlying TAD formation are also complex and not yet fully elucidated, though a number of [[protein complex]]es 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.<ref name=":2">{{cite journal | vauthors = Dixon JR, Gorkin DU, Ren B | title = Chromatin Domains: The Unit of Chromosome Organization | journal = Molecular Cell | volume = 62 | issue = 5 | pages = 668–680 | date = June 2016 | pmid = 27259200 | pmc = 5371509 | doi = 10.1016/j.molcel.2016.05.018 }}</ref> Furthermore, it has been proposed that the stiffness of TAD boundaries itself could cause the domain insulation and TAD formation.<ref name=":2" />