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Topologically associating domain

Topologically associating domains within chromosome territories, their borders and interactions

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 average size of a topologically associating domain (TAD) is 1000 kb in humans, 880 kb in mouse cells, and 140 kb in fruit flies.[2][3] Boundaries at both side of 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.[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.[4][5]

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-promoter interaction to each TAD;[6] however, a recent study uncouples TAD organization and gene expression.[7] Disruption of TAD boundaries are found to be associated with wide range of diseases such as cancer,[8][9][10] variety of limb malformations such as synpolydactyly, Cooks syndrome, and F-syndrome,[11] and number of brain disorders like Hypoplastic corpus callosum and Adult-onset demyelinating leukodystrophy.[11] Furthermore, studies have revealed that interactions between promoters and enhancers spanning single or multiple TADs, are fundamental to the exact dynamics of gene expression.[12] The genomic elements underlying these interactions are named distal tethering elements (DTEs) and it has been shown that these elements are important for precise gene activation of Hox genes in early embryogenesis of D. melanogaster.[12]

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 describe the TAD formation by the aid of CTCF and cohesin proteins.[13] Furthermore, it has been proposed that the stiffness of TAD boundaries itself could cause the domain insulation and TAD formation.[13]

  1. ^ a b Pombo A, Dillon N (April 2015). "Three-dimensional genome architecture: players and mechanisms". Nature Reviews. Molecular Cell Biology. 16 (4): 245–257. doi:10.1038/nrm3965. PMID 25757416. S2CID 6713103.
  2. ^ a b Yu M, Ren B (October 2017). "The Three-Dimensional Organization of Mammalian Genomes". Annual Review of Cell and Developmental Biology. 33: 265–289. doi:10.1146/annurev-cellbio-100616-060531. PMC 5837811. PMID 28783961.
  3. ^ Smirnov, Dmitrii N.; Kononkova, Anna D.; Toiber, Debra; Gelfand, Mikhail S.; Khrameeva, Ekaterina E. (2024-01-29), optimalTAD: annotation of topologically associating domains based on chromatin marks enrichment, doi:10.1101/2023.03.06.531254, retrieved 2024-10-09
  4. ^ Nora EP, Lajoie BR, Schulz EG, Giorgetti L, Okamoto I, Servant N, et al. (April 2012). "Spatial partitioning of the regulatory landscape of the X-inactivation centre". Nature. 485 (7398): 381–385. Bibcode:2012Natur.485..381N. doi:10.1038/nature11049. PMC 3555144. PMID 22495304.
  5. ^ Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. (April 2012). "Topological domains in mammalian genomes identified by analysis of chromatin interactions". Nature. 485 (7398): 376–380. Bibcode:2012Natur.485..376D. doi:10.1038/nature11082. PMC 3356448. PMID 22495300.
  6. ^ Krijger PH, de Laat W (December 2016). "Regulation of disease-associated gene expression in the 3D genome". Nature Reviews. Molecular Cell Biology. 17 (12): 771–782. doi:10.1038/nrm.2016.138. PMID 27826147. S2CID 11484886.
  7. ^ Ghavi-Helm Y; Jankowski A; Meiers S; Viales RR; Korbel JO; Furlong EE (August 2019). "Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression". Nature Genetics. 51 (8): 1272–1282. doi:10.1038/s41588-019-0462-3. PMC 7116017. PMID 31308546.
  8. ^ Corces MR, Corces VG (February 2016). "The three-dimensional cancer genome". Current Opinion in Genetics & Development. 36: 1–7. doi:10.1016/j.gde.2016.01.002. PMC 4880523. PMID 26855137.
  9. ^ Valton AL; Dekker J (February 2016). "TAD disruption as oncogenic driver". Current Opinion in Genetics & Development. 36: 34–40. doi:10.1016/j.gde.2016.03.008. PMC 4880504. PMID 27111891.
  10. ^ Achinger-Kawecka J, Clark SJ (January 2017). "Disruption of the 3D cancer genome blueprint". Epigenomics. 9 (1): 47–55. doi:10.2217/epi-2016-0111. PMID 27936932.
  11. ^ a b Spielmann M, Lupiáñez DG, Mundlos S (July 2018). "Structural variation in the 3D genome". Nature Reviews. Genetics. 19 (7): 453–467. doi:10.1038/s41576-018-0007-0. hdl:21.11116/0000-0003-610A-5. PMID 29692413. S2CID 22325904.
  12. ^ a b Batut, Philippe J.; Bing, Xin Yang; Sisco, Zachary; Raimundo, João; Levo, Michal; Levine, Michael S. (2022-02-04). "Genome organization controls transcriptional dynamics during development". Science. 375 (6580): 566–570. Bibcode:2022Sci...375..566B. doi:10.1126/science.abi7178. ISSN 0036-8075. PMC 10368186. PMID 35113722.
  13. ^ a b Dixon JR, Gorkin DU, Ren B (June 2016). "Chromatin Domains: The Unit of Chromosome Organization". Molecular Cell. 62 (5): 668–680. doi:10.1016/j.molcel.2016.05.018. PMC 5371509. PMID 27259200.

Topologically associating domain

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