Topologically Associating Domain

"Topologically associating domains" (TADs) are a way of understanding the organization of mammalian genomes as being split up into "chromosome neighborhoods" within which most enhancer-promoter contact occurs. They can range in size from thousands to millions of DNA bases. TADs are separated from each other by boundary regions enriched for transfer RNA genes and for binding of the transcription factor CTCF.[1]

Conservation in mammalian genomes

TADs have been reported to be relatively constant in different cell types (in stem cells and blood cells, for example). Besides, research indicates TAD may become more complex through evolution. Only one single chromatin regulatory compartment for Hox gene cluster found in amphioxus, while bimodal regulation in vertebrates infers vertebrates growing complicated limb structure during development may attribute to a more meticulous gene regulation through chromatin architecture evolution.[2]

Relationship to 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.[3]

Role in disease

Genomic structural variants that disrupt TAD boundaries have been reported to cause developmental disorders such as human limb malformations.[4] Recent research also illustrates TAD boundaries disorders are related to cancer such as T-cell acute lymphoblastic leukemia(T-ALL)[5] and gliomas.[6]

References

  1. ↑ Dixon, J. R.; Selvaraj, S; Yue, F; Kim, A; Li, Y; Shen, Y; Hu, M; Liu, J. S.; Ren, B (2012). "Topological domains in mammalian genomes identified by analysis of chromatin interactions". Nature 485 (7398): 376–80. doi:10.1038/nature11082. PMC 3356448. PMID 22495300.
  2. ↑ Acemel, Rafael D.; Tena, Juan J.; Irastorza-Azcarate, Ibai; Marlétaz, Ferdinand; Gómez-Marín, Carlos; de la Calle-Mustienes, Elisa; Bertrand, Stéphanie; Diaz, Sergio G.; Aldea, Daniel (2016-03-01). "A single three-dimensional chromatin compartment in amphioxus indicates a stepwise evolution of vertebrate Hox bimodal regulation". Nature Genetics 48 (3): 336–341. doi:10.1038/ng.3497. ISSN 1061-4036.
  3. ↑ Pope, B. D.; Ryba, T; Dileep, V; Yue, F; Wu, W; Denas, O; Vera, D. L.; Wang, Y; Hansen, R. S.; Canfield, T. K.; Thurman, R. E.; Cheng, Y; Gülsoy, G; Dennis, J. H.; Snyder, M. P.; Stamatoyannopoulos, J. A.; Taylor, J; Hardison, R. C.; Kahveci, T; Ren, B; Gilbert, D. M. (2014). "Topologically associating domains are stable units of replication-timing regulation". Nature 515 (7527): 402–5. doi:10.1038/nature13986. PMC 4251741. PMID 25409831.
  4. ↑ Lupiáñez, D. G.; Kraft, K; Heinrich, V; Krawitz, P; Brancati, F; Klopocki, E; Horn, D; Kayserili, H; Opitz, J. M.; Laxova, R; Santos-Simarro, F; Gilbert-Dussardier, B; Wittler, L; Borschiwer, M; Haas, S. A.; Osterwalder, M; Franke, M; Timmermann, B; Hecht, J; Spielmann, M; Visel, A; Mundlos, S (2015). "Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions". Cell 161 (5): 1012–1025. doi:10.1016/j.cell.2015.04.004. PMID 25959774.
  5. ↑ Hnisz, Denes; Weintraub, Abraham S.; Day, Daniel S.; Valton, Anne-Laure; Bak, Rasmus O.; Li, Charles H.; Goldmann, Johanna; Lajoie, Bryan R.; Fan, Zi Peng (2016-03-03). "Activation of proto-oncogenes by disruption of chromosome neighborhoods". Science: aad9024. doi:10.1126/science.aad9024. ISSN 0036-8075. PMID 26940867.
  6. ↑ Flavahan, William A.; Drier, Yotam; Liau, Brian B.; Gillespie, Shawn M.; Venteicher, Andrew S.; Stemmer-Rachamimov, Anat O.; Suvà, Mario L.; Bernstein, Bradley E. (2016-01-07). "Insulator dysfunction and oncogene activation in IDH mutant gliomas". Nature 529 (7584): 110–114. doi:10.1038/nature16490. ISSN 0028-0836.
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