Topologically associating domain

Topologically associating domains (TADs) are genomic regions ("chromosome neighborhoods") used to summarize the three-dimensional nuclear organization of mammalian genomes. A TAD represents a region of DNA within which physical interactions occur relatively frequently, whereas interactions across a TAD boundary occur relatively infrequently.[1] TADs can range in size from thousands to millions of DNA bases.

The mechanisms behind TAD formation are complex and not yet fully elucidated, though a number of factors are known to be associated with TAD formation: for example, CTCF and cohesin.[1] Similarly, the factors that denote TAD boundaries are also unknown, though TAD boundary regions have been shown to be enriched for CTCF binding. Certain genes have also been shown to be enriched near TAD boundaries, such as transfer RNA genes and housekeeping genes.[2][3]

Discovery and definition

TADs are defined as regions whose DNA sequences preferentially contact each other, using Hi-C data.[4] They have been shown to be present in drosophila,[5] mouse[6] and human[2] genomes, but not in Saccharomyces cerevisiae.[1]

TAD calling

To determine TAD locations, or "call TADs", an algorithm is applied to Hi-C data.

TADs are often called according to the method in Dixon et al (2012), using the so-called "directionality index".[2] 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.

Properties of TADs

Conservation

TADs have been reported to be relatively constant in different cell types (in stem cells and blood cells, for example).

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.[7] Insulated neighborhoods, DNA loops formed by CTCF/cohesin-bound regions, are proposed to functionally underlie TADs.[8]

Role in disease

Disruption of TAD boundaries can affect the expression of nearby genes, and this can cause disease.[9]

For example, genomic structural variants that disrupt TAD boundaries have been reported to cause developmental disorders such as human limb malformations.[10] Additionally, it has been claimed that disruption of TAD boundaries can provide growth advantages to certain cancers, such as T-cell acute lymphoblastic leukemia(T-ALL),[11] gliomas,[12] and colorectal cancer.[13]

See also

References

  1. 1 2 3 Pombo, A; Dillon, N (April 2015). "Three-dimensional genome architecture: players and mechanisms.". Nature reviews. Molecular cell biology. 16 (4): 245–57. doi:10.1038/nrm3965. PMID 25757416.
  2. 1 2 3 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 3356448Freely accessible. PMID 22495300.
  3. ↑ 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, Edith (2012). "Spatial partitioning of the regulatory landscape of the X-inactivation centre". Nature. 485 (7398): 381–5. doi:10.1038/nature11049. PMC 3555144Freely accessible. PMID 22495304.
  4. ↑ de Laat, Wouter; Duboule, Denis (23 October 2013). "Topology of mammalian developmental enhancers and their regulatory landscapes". Nature. 502 (7472): 499–506. doi:10.1038/nature12753. PMID 24153303.
  5. ↑ Sexton, Tom; Yaffe, Eitan; Kenigsberg, Ephraim; Bantignies, Frédéric; Leblanc, Benjamin; Hoichman, Michael; Parrinello, Hugues; Tanay, Amos; Cavalli, Giacomo (February 2012). "Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome". Cell. 148 (3): 458–472. doi:10.1016/j.cell.2012.01.010. PMID 22265598.
  6. ↑ Nora, Elphège P.; Lajoie, Bryan R.; Schulz, Edda G.; Giorgetti, Luca; Okamoto, Ikuhiro; Servant, Nicolas; Piolot, Tristan; van Berkum, Nynke L.; Meisig, Johannes; Sedat, John; Gribnau, Joost; Barillot, Emmanuel; Blüthgen, Nils; Dekker, Job; Heard, Edith (11 April 2012). "Spatial partitioning of the regulatory landscape of the X-inactivation centre". Nature. 485 (7398): 381–385. doi:10.1038/nature11049. PMC 3555144Freely accessible. PMID 22495304.
  7. ↑ 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 4251741Freely accessible. PMID 25409831.
  8. ↑ Ji, X; Dadon, DB; Powell, BE; Fan, ZP; Borges-Rivera, D; Shachar, S; Weintraub, AS; Hnisz, D; Pegoraro, G; Lee, TI; Misteli, T; Jaenisch, R; Young, RA (4 February 2016). "3D Chromosome Regulatory Landscape of Human Pluripotent Cells.". Cell stem cell. 18 (2): 262–75. PMID 26686465.
  9. ↑ Lupiáñez, Darío G.; Spielmann, Malte; Mundlos, Stefan (April 2016). "Breaking TADs: How Alterations of Chromatin Domains Result in Disease". Trends in Genetics. 32 (4): 225–237. doi:10.1016/j.tig.2016.01.003.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Weischenfeldt, Joachim; Dubash, Taronish; Drainas, Alexandros P.; Mardin, Balca R.; Chen, Yuanyuan; Stütz, Adrian M.; Waszak, Sebsatian M.; Bosco, Graziella; Halvorsen, Ann R.; Raeder, Benjamin; Efthymiopoulos, Theocharis; Erkek, Serap; Siegl, Christine; Brenner, Hermann; Brustugun, Odd T.; Dieter, Sebastian M; Northcott, Paul A.; Petersen, Iver; Pfister, Stefan M.; Schneider, Martin; Solberg, Steinar K.; Thunissen, Erik; Weichert, Wilko; Zichner, Thomas; Thomas, Roman; Peifer, Martin; Helland, Aslaug; Ball, Claudia R.; Jechlinger, Martin; Sotillo, Rocio; Glimm, Hanno; Korbel, Jan O. (2016). "Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking". Nature Genetics. doi:10.1038/ng.3722. PMID 27869826.
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