Biology:Topologically associating domain
![](/wiki/images/thumb/b/be/Structural_organization_of_chromatin.png/300px-Structural_organization_of_chromatin.png)
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 median size of a TAD in mouse cells is 880 kb, and they have similar sizes in non-mammalian species.[2] 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.[3][4]
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;[5] however, a recent study uncouples TAD organization and gene expression.[6] Disruption of TAD boundaries are found to be associated with wide range of diseases such as cancer,[7][8][9] variety of limb malformations such as synpolydactyly, Cooks syndrome, and F-syndrome,[10] and number of brain disorders like Hypoplastic corpus callosum and Adult-onset demyelinating leukodystrophy.[10]
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.[11] Furthermore, it has been proposed that the stiffness of TAD boundaries itself could cause the domain insulation and TAD formation.[11]
Discovery and diversity
TADs are defined as regions whose DNA sequences preferentially contact each other. They were discovered in 2012 using chromosome conformation capture techniques including Hi-C.[3][12][4] They have been shown to be present in multiple species,[13] including fruit flies (Drosophila),[14] mouse,[3] plants, fungi and human[4] genomes. In bacteria, they are referred to as Chromosomal Interacting Domains (CIDs).[13]
Analytical tools and databases
TAD locations are defined by applying an algorithm to Hi-C data. For example, TADs are often called according to the so-called "directionality index".[4] 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.
The development of specialized genome browsers and visualization tools[15] such as Juicebox,[16] HiGlass[17]/HiPiler,[18] The 3D Genome Browser,[19] 3DIV,[20] 3D-GNOME,[21] and TADKB[22] have enabled us to visualize the TAD organization of regions of interest in different cell types.
Mechanisms of formation
A number of proteins are known to be associated with TAD formation including the protein CTCF and the protein complex cohesin.[1] It is also unknown what components are required at TAD boundaries; however, in mammalian cells, it has been shown that these boundary regions have comparatively high levels of CTCF binding. 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.[3][4]
Computer simulations have shown that chromatin loop extrusion driven by cohesin motors can generate TADs.[23][24] In the loop extrusion model, cohesin binds chromatin, pulls it in, and extrudes chromatin to progressively grow a loop. Chromatin on both sides of the cohesin complex is extruded until cohesin encounters a chromatin-bound CTCF protein, typically located at the boundary of a TAD. In this way, TAD boundaries can be brought together as the anchors of a chromatin loop.[25] Indeed, in vitro, cohesin has been observed to processively extrude DNA loops in an ATP-dependent manner[26][27][28] and stall at CTCF.[29][30] However, some in vitro data indicates that the observed loops may be artifacts.[31][32] Importantly, since cohesins can dynamically unbind from chromatin, this model suggests that TADs (and associated chromatin loops) are dynamic, transient structures,[23] in agreement with in vivo observations.[33][34][35][36]
Other mechanisms for TAD formation have been suggested. For example, some simulations suggest that transcription-generated supercoiling can relocalize cohesin to TAD boundaries[37][38] or that passively diffusing cohesin “slip links”[39][40] can generate TADs.
Properties
Conservation
TADs have been reported to be relatively constant between different cell types (in stem cells and blood cells, for example), and even between species in specific cases.[4][41][42][43]
Relationship with promoter-enhancer contacts
The majority of observed interactions between promoters and enhancers do not cross TAD boundaries. Removing a TAD boundary (for example, using CRISPR to delete the relevant region of the genome) can allow new promoter-enhancer contacts to form. This can affect gene expression nearby - such misregulation has been shown to cause limb malformations (e.g. polydactyly) in humans and mice.[42]
Computer simulations have shown that transcription-induced supercoiling of chromatin fibres can explain how TADs are formed and how they can assure very efficient interactions between enhancers and their cognate promoters located in the same TAD.[44]
Relationship with other structural features of the genome
Replication timing domains have been shown to be associated with TADs as their boundary is co localized with the boundaries of TADs that are located at either sides of compartments.[45] Insulated neighborhoods, DNA loops formed by CTCF/cohesin-bound regions, are proposed to functionally underlie TADs.[46]
Role in disease
Disruption of TAD boundaries can affect the expression of nearby genes, and this can cause disease.[47]
For example, genomic structural variants that disrupt TAD boundaries have been reported to cause developmental disorders such as human limb malformations.[48][49][50] Additionally, several studies have provided evidence that the disruption or rearrangement of TAD boundaries can provide growth advantages to certain cancers, such as T-cell acute lymphoblastic leukemia (T-ALL),[51] gliomas,[52] and lung cancer.[53]
Lamina-associated domains
Lamina-associated domains (LADs) are parts of the chromatin that heavily interact with the lamina, a network-like structure at the inner membrane of the nucleus.[54] LADs consist mostly of transcriptionally silent chromatin, being enriched with trimethylated Lys27 on histone H3, (ie H3K27me3); which is a common posttranslational histone modification of heterochromatin.[55] LADs have CTCF-binding sites at their periphery.[54]
See also
References
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- ↑ 2.0 2.1 "The Three-Dimensional Organization of Mammalian Genomes". Annual Review of Cell and Developmental Biology 33: 265–289. October 2017. doi:10.1146/annurev-cellbio-100616-060531. PMID 28783961.
- ↑ 3.0 3.1 3.2 3.3 "Spatial partitioning of the regulatory landscape of the X-inactivation centre". Nature 485 (7398): 381–385. April 2012. doi:10.1038/nature11049. PMID 22495304. Bibcode: 2012Natur.485..381N.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Topological domains in mammalian genomes identified by analysis of chromatin interactions". Nature 485 (7398): 376–380. April 2012. doi:10.1038/nature11082. PMID 22495300. Bibcode: 2012Natur.485..376D.
- ↑ "Regulation of disease-associated gene expression in the 3D genome". Nature Reviews. Molecular Cell Biology 17 (12): 771–782. December 2016. doi:10.1038/nrm.2016.138. PMID 27826147.
- ↑ 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. PMID 31308546.
- ↑ "The three-dimensional cancer genome". Current Opinion in Genetics & Development 36: 1–7. February 2016. doi:10.1016/j.gde.2016.01.002. PMID 26855137.
- ↑ "TAD disruption as oncogenic driver". Current Opinion in Genetics & Development 36: 34–40. February 2016. doi:10.1016/j.gde.2016.03.008. PMID 27111891.
- ↑ "Disruption of the 3D cancer genome blueprint". Epigenomics 9 (1): 47–55. January 2017. doi:10.2217/epi-2016-0111. PMID 27936932.
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- ↑ 11.0 11.1 "Chromatin Domains: The Unit of Chromosome Organization". Molecular Cell 62 (5): 668–680. June 2016. doi:10.1016/j.molcel.2016.05.018. PMID 27259200.
- ↑ "Topology of mammalian developmental enhancers and their regulatory landscapes". Nature 502 (7472): 499–506. October 2013. doi:10.1038/nature12753. PMID 24153303. Bibcode: 2013Natur.502..499D.
- ↑ 13.0 13.1 "Principles of genome folding into topologically associating domains". Science Advances 5 (4): eaaw1668. April 2019. doi:10.1126/sciadv.aaw1668. PMID 30989119. Bibcode: 2019SciA....5.1668S.
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- ↑ "Visualising three-dimensional genome organisation in two dimensions". Development 146 (19): 99–101. September 2019. doi:10.1242/dev.177162. PMID 31558569.
- ↑ Durand NC; Robinson JT; Shamim MS; Machol I; Mesirov JP; Lander ES; Aiden EL (July 2016). "Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom". Cell Systems 3 (1): 99–101. doi:10.1016/j.cels.2015.07.012. PMID 27467250.
- ↑ "HiGlass: web-based visual exploration and analysis of genome interaction maps". Genome Biology 19 (1): 125. August 2018. doi:10.1186/s13059-018-1486-1. PMID 30143029.
- ↑ "HiPiler: Visual Exploration of Large Genome Interaction Matrices with Interactive Small Multiples". IEEE Transactions on Visualization and Computer Graphics 24 (1): 522–531. January 2018. doi:10.1109/TVCG.2017.2745978. PMID 28866592.
- ↑ "The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions". Genome Biology 19 (1): 151. October 2018. doi:10.1186/s13059-018-1519-9. PMID 30286773.
- ↑ "3DIV: A 3D-genome Interaction Viewer and database". Nucleic Acids Research 46 (D1): D52–D57. January 2018. doi:10.1093/nar/gkx1017. PMID 29106613.
- ↑ "3D-GNOME: an integrated web service for structural modeling of the 3D genome". Nucleic Acids Research 44 (W1): W288–W293. July 2016. doi:10.1093/nar/gkw437. PMID 27185892.
- ↑ Liu, T., Porter, J., Zhao, C. et al. TADKB: Family classification and a knowledge base of topologically associating domains. BMC Genomics 20, 217 (2019). https://doi.org/10.1186/s12864-019-5551-2
- ↑ 23.0 23.1 "Formation of Chromosomal Domains by Loop Extrusion". Cell Reports 15 (9): 2038–2049. May 2016. doi:10.1016/j.celrep.2016.04.085. PMID 27210764.
- ↑ Sanborn AL; Rao SS; Huang SC; Durand NC; Huntley MH; Jewett AI et al. (November 2015). "Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes". Proceedings of the National Academy of Sciences of the United States of America 112 (47): E6456–E6465. doi:10.1073/pnas.1518552112. PMID 26499245. Bibcode: 2015PNAS..112E6456S.
- ↑ Yatskevich S; Rhodes J; Nasmyth K (December 2019). "Organization of Chromosomal DNA by SMC Complexes". Annual Review of Genetics 53 (1): 445–482. doi:10.1146/annurev-genet-112618-043633. PMID 31577909.
- ↑ "Cohesin and condensin extrude DNA loops in a cell cycle-dependent manner". eLife 9: e53885. May 2020. doi:10.7554/eLife.53885. PMID 32396063.
- ↑ "DNA loop extrusion by human cohesin". Science 366 (6471): 1338–1345. December 2019. doi:10.1126/science.aaz3418. PMID 31753851. Bibcode: 2019Sci...366.1338D.
- ↑ "Human cohesin compacts DNA by loop extrusion". Science 366 (6471): 1345–1349. December 2019. doi:10.1126/science.aaz4475. PMID 31780627. Bibcode: 2019Sci...366.1345K.
- ↑ Davidson IF, Barth R, Zaczek M, van der Torre J, Tang W, Nagasaka K, et al. (2022-09-09). "CTCF is a DNA-tension-dependent barrier to cohesin-mediated DNA loop extrusion". bioRxiv 10.1101/2022.09.08.507093.
- ↑ Zhang H, Shi Z, Banigan EJ, Kim Y, Yu H, Bai X, Finkelstein IJ (2022-10-07). "CTCF and R-loops are boundaries of cohesin-mediated DNA looping". bioRxiv 10.1101/2022.09.15.508177.
- ↑ Man, Zhou (September 2022). "DNA sliding and loop formation by E. coli SMC complex: MukBEF". Biochemistry and Biophysics Reports 31: 101297. doi:10.1016/j.bbrep.2022.101297. PMID 35770038.
- ↑ "Bridging-induced phase separation induced by cohesin SMC protein complexes". Science Advances 7 (7): eabe5905. February 2021. doi:10.1126/sciadv.abe5905. PMID 33568486. Bibcode: 2021SciA....7.5905R.
- ↑ "Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging". Science 376 (6592): 496–501. April 2022. doi:10.1126/science.abn6583. PMID 35420890. Bibcode: 2022Sci...376..496G.
- ↑ Beckwith KS, Ødegård-Fougner Ø, Morero NR, Barton C, Schueder F, Tang W, et al. (2022-05-02). "Visualization of loop extrusion by DNA nanoscale tracing in single human cells". bioRxiv 10.1101/2021.04.12.439407.
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- ↑ "Are TADs supercoiled?". Nucleic Acids Research 47 (2): 521–532. January 2019. doi:10.1093/nar/gky1091. PMID 30395328.
- ↑ "Transcription-induced supercoiling as the driving force of chromatin loop extrusion during formation of TADs in interphase chromosomes". Nucleic Acids Research 46 (4): 1648–1660. February 2018. doi:10.1093/nar/gkx1123. PMID 29140466.
- ↑ "Nonequilibrium Chromosome Looping via Molecular Slip Links". Physical Review Letters 119 (13): 138101. September 2017. doi:10.1103/PhysRevLett.119.138101. PMID 29341686. Bibcode: 2017PhRvL.119m8101B.
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- ↑ "Are TADs supercoiled?". Nucleic Acids Research 47 (2): 521–532. January 2019. doi:10.1093/nar/gky1091. PMID 30395328.
- ↑ "Control of DNA replication timing in the 3D genome". Nature Reviews. Molecular Cell Biology 20 (12): 721–737. December 2019. doi:10.1038/s41580-019-0162-y. PMID 31477886.
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- ↑ "Breaking TADs: How Alterations of Chromatin Domains Result in Disease". Trends in Genetics 32 (4): 225–237. April 2016. doi:10.1016/j.tig.2016.01.003. PMID 26862051.
- ↑ "Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions". Cell 161 (5): 1012–1025. May 2015. doi:10.1016/j.cell.2015.04.004. PMID 25959774.
- ↑ "A Family's Shared Defect Sheds Light on the Human Genome". The New York Times. 2017-01-09. https://www.nytimes.com/2017/01/09/science/dna-tads.html?mcubz=1.
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External links
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