topologically associating domain
{{short description|Self-interacting genomic region}}
File:Structural organization of chromatin.png, 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.{{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 }} 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.{{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 }}{{Citation |last1=Smirnov |first1=Dmitrii N. |title=optimalTAD: annotation of topologically associating domains based on chromatin marks enrichment |date=2024-01-29 |url=https://www.biorxiv.org/content/10.1101/2023.03.06.531254v2 |access-date=2024-10-09 |language=en |doi=10.1101/2023.03.06.531254 |last2=Kononkova |first2=Anna D. |last3=Toiber |first3=Debra |last4=Gelfand |first4=Mikhail S. |last5=Khrameeva |first5=Ekaterina E.}} Boundaries at both side of these domains are conserved between different mammalian cell types and even across species and are highly enriched with CCCTC-binding factor (CTCF) and cohesin. 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.{{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 }}{{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 }}
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;{{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 }} however, a recent study uncouples TAD organization and gene expression.{{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 }} Disruption of TAD boundaries are found to be associated with wide range of diseases such as cancer,{{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 }}{{cite journal | author1 = Valton AL| author2 = Dekker J| author-link2 =Job Dekker | 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 }}{{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 }} variety of limb malformations such as synpolydactyly, Cooks syndrome, and F-syndrome,{{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 }} and number of brain disorders like Hypoplastic corpus callosum and Adult-onset demyelinating leukodystrophy. Furthermore, studies have revealed that interactions between promoters and enhancers spanning single or multiple TADs, are fundamental to the exact dynamics of gene expression.{{Cite journal |last1=Batut |first1=Philippe J. |last2=Bing |first2=Xin Yang |last3=Sisco |first3=Zachary |last4=Raimundo |first4=João |last5=Levo |first5=Michal |last6=Levine |first6=Michael S. |date=2022-02-04 |title=Genome organization controls transcriptional dynamics during development |journal=Science |language=en |volume=375 |issue=6580 |pages=566–570 |doi=10.1126/science.abi7178 |issn=0036-8075 |pmc=10368186 |pmid=35113722|bibcode=2022Sci...375..566B }} 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.
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.{{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 }} Furthermore, it has been proposed that the stiffness of TAD boundaries itself could cause the domain insulation and TAD formation.
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.{{cite journal | vauthors = de Laat W, Duboule D | title = Topology of mammalian developmental enhancers and their regulatory landscapes | journal = Nature | volume = 502 | issue = 7472 | pages = 499–506 | date = October 2013 | pmid = 24153303 | doi = 10.1038/nature12753 | s2cid = 4468533 | bibcode = 2013Natur.502..499D }} They have been shown to be present in multiple species,{{cite journal | vauthors = Szabo Q, Bantignies F, Cavalli G | title = Principles of genome folding into topologically associating domains | journal = Science Advances | volume = 5 | issue = 4 | pages = eaaw1668 | date = April 2019 | pmid = 30989119 | pmc = 6457944 | doi = 10.1126/sciadv.aaw1668 | bibcode = 2019SciA....5.1668S }} including fruit flies (Drosophila),{{cite journal | vauthors = Sexton T, Yaffe E, Kenigsberg E, Bantignies F, Leblanc B, Hoichman M, Parrinello H, Tanay A, Cavalli G | display-authors = 6 | title = Three-dimensional folding and functional organization principles of the Drosophila genome | journal = Cell | volume = 148 | issue = 3 | pages = 458–472 | date = February 2012 | pmid = 22265598 | doi = 10.1016/j.cell.2012.01.010 | doi-access = free }} mouse, plants, fungi and human genomes. In bacteria, they are referred to as Chromosomal Interacting Domains (CIDs).
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". 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{{cite journal | vauthors = Ing-Simmons E, Vaquerizas JM | title = Visualising three-dimensional genome organisation in two dimensions | journal = Development | volume = 146 | issue = 19 | pages = 99–101 | date = September 2019 | pmid = 31558569 | doi = 10.1242/dev.177162 | doi-access = free }} such as Juicebox,{{cite journal | author1 = Durand NC | author2 = Robinson JT | author3 = Shamim MS| author4 = Machol I| author5 = Mesirov JP| author6 = Lander ES| author7 = Aiden EL | author-link7 = Erez Lieberman Aiden| title = Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom | journal = Cell Systems | volume = 3 | issue = 1 | pages = 99–101 | date = July 2016 | pmid = 27467250 | pmc = 5596920 | doi = 10.1016/j.cels.2015.07.012 }} HiGlass{{cite journal | vauthors = Kerpedjiev P, Abdennur N, Lekschas F, McCallum C, Dinkla K, Strobelt H, Luber JM, Ouellette SB, Azhir A, Kumar N, Hwang J, Lee S, Alver BH, Pfister H, Mirny LA, Park PJ, Gehlenborg N | display-authors = 6 | title = HiGlass: web-based visual exploration and analysis of genome interaction maps | journal = Genome Biology | volume = 19 | issue = 1 | pages = 125 | date = August 2018 | pmid = 30143029 | pmc = 6109259 | doi = 10.1186/s13059-018-1486-1 | doi-access = free }}/HiPiler,{{cite journal | vauthors = Lekschas F, Bach B, Kerpedjiev P, Gehlenborg N, Pfister H | title = HiPiler: Visual Exploration of Large Genome Interaction Matrices with Interactive Small Multiples | journal = IEEE Transactions on Visualization and Computer Graphics | volume = 24 | issue = 1 | pages = 522–531 | date = January 2018 | pmid = 28866592 | pmc = 6038708 | doi = 10.1109/TVCG.2017.2745978 }} The 3D Genome Browser,{{cite journal | vauthors = Wang Y, Song F, Zhang B, Zhang L, Xu J, Kuang D, Li D, Choudhary MN, Li Y, Hu M, Hardison R, Wang T, Yue F | display-authors = 6 | title = The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions | journal = Genome Biology | volume = 19 | issue = 1 | pages = 151 | date = October 2018 | pmid = 30286773 | pmc = 6172833 | doi = 10.1186/s13059-018-1519-9 | doi-access = free }} 3DIV,{{cite journal | vauthors = Yang D, Jang I, Choi J, Kim MS, Lee AJ, Kim H, Eom J, Kim D, Jung I, Lee B | display-authors = 6 | title = 3DIV: A 3D-genome Interaction Viewer and database | journal = Nucleic Acids Research | volume = 46 | issue = D1 | pages = D52–D57 | date = January 2018 | pmid = 29106613 | pmc = 5753379 | doi = 10.1093/nar/gkx1017 }} 3D-GNOME,{{cite journal | vauthors = Szalaj P, Michalski PJ, Wróblewski P, Tang Z, Kadlof M, Mazzocco G, Ruan Y, Plewczynski D | display-authors = 6 | title = 3D-GNOME: an integrated web service for structural modeling of the 3D genome | journal = Nucleic Acids Research | volume = 44 | issue = W1 | pages = W288–W293 | date = July 2016 | pmid = 27185892 | pmc = 4987952 | doi = 10.1093/nar/gkw437 }} and TADKBLiu, T., Porter, J., Zhao, C. et al. [https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-019-5551-2 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 have enabled us to visualize the TAD organization of regions of interest in different cell types.
Mechanisms of formation
File:Cohesin-LoopExtrusion-EN.svg
A number of proteins are known to be associated with TAD formation including the protein CTCF and the protein complex cohesin. 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.
Computer simulations have shown that chromatin loop extrusion driven by cohesin motors can generate TADs.{{cite journal | vauthors = Fudenberg G, Imakaev M, Lu C, Goloborodko A, Abdennur N, Mirny LA | title = Formation of Chromosomal Domains by Loop Extrusion | journal = Cell Reports | volume = 15 | issue = 9 | pages = 2038–2049 | date = May 2016 | pmid = 27210764 | doi = 10.1016/j.celrep.2016.04.085 | pmc = 4889513 }}{{cite journal | author1 = Sanborn AL|author2 = Rao SS| author3 = Huang SC| author4 = Durand NC| author5 = Huntley MH| author6 = Jewett AI| author7 = Bochkov ID| author8 = Chinnappan D| author9 = Cutkosky A| author10= Li J| author11 = Geeting KP| author12 = Gnirke A| author13 = Melnikov A| author14 = McKenna D| author15 = Stamenova EK| author16 = Lander ES| author17 = Aiden EL|author-link17 =Erez Lieberman Aiden | display-authors = 6 | title = Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 47 | pages = E6456–E6465 | date = November 2015 | pmid = 26499245 | pmc = 4664323 | doi = 10.1073/pnas.1518552112 | bibcode = 2015PNAS..112E6456S | doi-access = free }} 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.{{cite journal | author1 = Yatskevich S | author2 = Rhodes J | author3 = Nasmyth K | author-link3 =Kim Nasmyth | title = Organization of Chromosomal DNA by SMC Complexes | journal = Annual Review of Genetics | volume = 53 | issue = 1 | pages = 445–482 | date = December 2019 | pmid = 31577909 | doi = 10.1146/annurev-genet-112618-043633 | s2cid = 203653572 | doi-access = free }} Indeed, in vitro, cohesin has been observed to processively extrude DNA loops in an ATP-dependent manner{{cite journal | vauthors = Golfier S, Quail T, Kimura H, Brugués J | title = Cohesin and condensin extrude DNA loops in a cell cycle-dependent manner | journal = eLife | volume = 9 | pages = e53885 | date = May 2020 | pmid = 32396063 | doi = 10.7554/eLife.53885 | pmc = 7316503 | veditors = Dekker, Struhl K, Mirny LA, Musacchio A, Marko JF | doi-access = free }}{{cite journal | vauthors = Davidson IF, Bauer B, Goetz D, Tang W, Wutz G, Peters JM | title = DNA loop extrusion by human cohesin | journal = Science | volume = 366 | issue = 6471 | pages = 1338–1345 | date = December 2019 | pmid = 31753851 | doi = 10.1126/science.aaz3418 | bibcode = 2019Sci...366.1338D | s2cid = 208228309 | doi-access = free }}{{cite journal | vauthors = Kim Y, Shi Z, Zhang H, Finkelstein IJ, Yu H | title = Human cohesin compacts DNA by loop extrusion | journal = Science | volume = 366 | issue = 6471 | pages = 1345–1349 | date = December 2019 | pmid = 31780627 | pmc = 7387118 | doi = 10.1126/science.aaz4475 | bibcode = 2019Sci...366.1345K }} and stall at CTCF.{{Cite bioRxiv | vauthors = Davidson IF, Barth R, Zaczek M, van der Torre J, Tang W, Nagasaka K, Janissen R, Kerssemakers J, Wutz G, Dekker C, Peters JM | display-authors = 6 |date=2022-09-09 |title=CTCF is a DNA-tension-dependent barrier to cohesin-mediated DNA loop extrusion |language=en |biorxiv =10.1101/2022.09.08.507093 }}{{Cite bioRxiv | vauthors = Zhang H, Shi Z, Banigan EJ, Kim Y, Yu H, Bai X, Finkelstein IJ |date=2022-10-07 |title=CTCF and R-loops are boundaries of cohesin-mediated DNA looping |language=en |biorxiv =10.1101/2022.09.15.508177}} However, some in vitro data indicates that the observed loops may be artifacts.{{cite journal |last=Man |first=Zhou |date=September 2022 |title=DNA sliding and loop formation by E. coli SMC complex: MukBEF |journal=Biochemistry and Biophysics Reports |volume=31 |pages=101297 |doi=10.1016/j.bbrep.2022.101297 |pmid=35770038|pmc=9234588 }}{{cite journal | vauthors = Ryu JK, Bouchoux C, Liu HW, Kim E, Minamino M, de Groot R, Katan AJ, Bonato A, Marenduzzo D, Michieletto D, Uhlmann F | title = Bridging-induced phase separation induced by cohesin SMC protein complexes | journal = Science Advances | volume = 7 | issue = 7 | pages = eabe5905 | date = February 2021| pmid = 33568486| doi = 10.1126/sciadv.abe5905 | pmc = 7875533 | bibcode = 2021SciA....7.5905R }} Importantly, since cohesins can dynamically unbind from chromatin, this model suggests that TADs (and associated chromatin loops) are dynamic, transient structures, in agreement with in vivo observations.{{cite journal | vauthors = Gabriele M, Brandão HB, Grosse-Holz S, Jha A, Dailey GM, Cattoglio C, Hsieh TS, Mirny L, Zechner C, Hansen AS | display-authors = 6 | title = Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging | journal = Science | volume = 376 | issue = 6592 | pages = 496–501 | date = April 2022 | pmid = 35420890 | pmc = 9069445 | doi = 10.1126/science.abn6583 | bibcode = 2022Sci...376..496G }}{{Cite bioRxiv | vauthors = Beckwith KS, Ødegård-Fougner Ø, Morero NR, Barton C, Schueder F, Tang W, Alexander S, Peters JM, Jungmann R, Birney E, Ellenberg J | display-authors = 6 |date=2022-05-02 |title=Visualization of loop extrusion by DNA nanoscale tracing in single human cells |language=en |biorxiv=10.1101/2021.04.12.439407 }}{{Cite bioRxiv | vauthors = Mach P, Kos PI, Zhan Y, Cramard J, Gaudin S, Tünnermann J, Marchi E, Eglinger J, Zuin J, Kryzhanovska M, Smallwood S, Gelman L, Roth G, Nora EP, Tiana G | display-authors = 6 |date=2022-03-03 |title=Live-cell imaging and physical modeling reveal control of chromosome folding dynamics by cohesin and CTCF |language=en |biorxiv =10.1101/2022.03.03.482826}}{{cite journal | vauthors = Flyamer IM, Gassler J, Imakaev M, Brandão HB, Ulianov SV, Abdennur N, Razin SV, Mirny LA, Tachibana-Konwalski K | display-authors = 6 | title = Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition | journal = Nature | volume = 544 | issue = 7648 | pages = 110–114 | date = April 2017 | pmid = 28355183 | doi = 10.1038/nature21711 | pmc = 5639698 | bibcode = 2017Natur.544..110F }}
Other mechanisms for TAD formation have been suggested. For example, some simulations suggest that transcription-generated supercoiling can relocalize cohesin to TAD boundaries{{cite journal | vauthors = Racko D, Benedetti F, Dorier J, Stasiak A | title = Transcription-induced supercoiling as the driving force of chromatin loop extrusion during formation of TADs in interphase chromosomes | journal = Nucleic Acids Research | volume = 46 | issue = 4 | pages = 1648–1660 | date = February 2018 | pmid = 29140466 | pmc = 5829651 | doi = 10.1093/nar/gkx1123 }} or that passively diffusing cohesin “slip links”{{cite journal | vauthors = Brackley CA, Johnson J, Michieletto D, Morozov AN, Nicodemi M, Cook PR, Marenduzzo D | title = Nonequilibrium Chromosome Looping via Molecular Slip Links | journal = Physical Review Letters | volume = 119 | issue = 13 | pages = 138101 | date = September 2017 | pmid = 29341686 | doi = 10.1103/PhysRevLett.119.138101 | arxiv = 1612.07256 | bibcode = 2017PhRvL.119m8101B | s2cid = 14706723 }}{{cite journal | vauthors = Yamamoto T, Schiessel H | title = Osmotic mechanism of the loop extrusion process | journal = Physical Review E | volume = 96 | issue = 3–1 | pages = 030402 | date = September 2017 | pmid = 29346962 | doi = 10.1103/PhysRevE.96.030402 | bibcode = 2017PhRvE..96c0402Y | hdl = 1887/58394 | hdl-access = free }} 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.{{cite journal | vauthors = Vietri Rudan M, Barrington C, Henderson S, Ernst C, Odom DT, Tanay A, Hadjur S | title = Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture | journal = Cell Reports | volume = 10 | issue = 8 | pages = 1297–1309 | date = March 2015 | pmid = 25732821 | pmc = 4542312 | doi = 10.1016/j.celrep.2015.02.004 }}{{cite journal | vauthors = Jost D, Vaillant C, Meister P | title = Coupling 1D modifications and 3D nuclear organization: data, models and function | journal = Current Opinion in Cell Biology | volume = 44 | pages = 20–27 | date = February 2017 | pmid = 28040646 | doi = 10.1016/j.ceb.2016.12.001 }}{{cite journal | vauthors = Yang Y, Zhang Y, Ren B, Dixon JR, Ma J | title = Comparing 3D Genome Organization in Multiple Species Using Phylo-HMRF | journal = Cell Systems | volume = 8 | issue = 6 | pages = 494–505.e14 | date = June 2019 | pmid = 31229558 | pmc = 6706282 | doi = 10.1016/j.cels.2019.05.011 }} Comparative TAD analysis between Drosophila melanogaster and Drosophila subobscura, with a divergence time of approximately 49 million years, has revealed a conservation in range of 30-40%.{{Cite journal |last1=Liao |first1=Yi |last2=Zhang |first2=Xinwen |last3=Chakraborty |first3=Mahul |last4=Emerson |first4=J. J. |date=2021-03-01 |title=Topologically associating domains and their role in the evolution of genome structure and function in Drosophila |url=https://genome.cshlp.org/content/31/3/397.abstract |journal=Genome Research |language=en |volume=31 |issue=3 |pages=397–410 |doi=10.1101/gr.266130.120 |issn=1088-9051 |pmid=33563719|pmc=7919452 }}
=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.
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.{{cite journal | vauthors = Racko D, Benedetti F, Dorier J, Stasiak A | title = Are TADs supercoiled? | journal = Nucleic Acids Research | volume = 47 | issue = 2 | pages = 521–532 | date = January 2019 | pmid = 30395328 | pmc = 6344874 | doi = 10.1093/nar/gky1091 }}
=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.{{cite journal | vauthors = Marchal C, Sima J, Gilbert DM | title = Control of DNA replication timing in the 3D genome | journal = Nature Reviews. Molecular Cell Biology | volume = 20 | issue = 12 | pages = 721–737 | date = December 2019 | pmid = 31477886 | doi = 10.1038/s41580-019-0162-y | s2cid = 201714312 | pmc = 11567694 }} Insulated neighborhoods, DNA loops formed by CTCF/cohesin-bound regions, are proposed to functionally underlie TADs.{{cite journal | vauthors = 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 | display-authors = 6 | title = 3D Chromosome Regulatory Landscape of Human Pluripotent Cells | journal = Cell Stem Cell | volume = 18 | issue = 2 | pages = 262–275 | date = February 2016 | pmid = 26686465 | pmc = 4848748 | doi = 10.1016/j.stem.2015.11.007 }}
Genome rearrangement breakpoint have shown to be enriched at the TAD boundaries in D. melanogaster.{{Cite journal |last1=Liao |first1=Yi |last2=Zhang |first2=Xinwen |last3=Chakraborty |first3=Mahul |last4=Emerson |first4=J. J. |date=2021-03-01 |title=Topologically associating domains and their role in the evolution of genome structure and function in Drosophila |url=https://genome.cshlp.org/content/31/3/397.abstract |journal=Genome Research |language=en |volume=31 |issue=3 |pages=397–410 |doi=10.1101/gr.266130.120 |issn=1088-9051 |pmid=33563719|pmc=7919452 }}
Role in disease
Disruption of TAD boundaries can affect the expression of nearby genes, and this can cause disease.{{cite journal | vauthors = Lupiáñez DG, Spielmann M, Mundlos S | title = Breaking TADs: How Alterations of Chromatin Domains Result in Disease | journal = Trends in Genetics | volume = 32 | issue = 4 | pages = 225–237 | date = April 2016 | pmid = 26862051 | doi = 10.1016/j.tig.2016.01.003 | hdl-access = free | hdl = 11858/00-001M-0000-002E-1D1D-D }}
For example, genomic structural variants that disrupt TAD boundaries have been reported to cause developmental disorders such as human limb malformations.{{cite journal | vauthors = Lupiáñez DG, Kraft K, Heinrich V, Krawitz P, Brancati F, Klopocki E, Horn D, Kayserili H, Opitz JM, Laxova R, Santos-Simarro F, Gilbert-Dussardier B, Wittler L, Borschiwer M, Haas SA, Osterwalder M, Franke M, Timmermann B, Hecht J, Spielmann M, Visel A, Mundlos S | display-authors = 6 | title = Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions | journal = Cell | volume = 161 | issue = 5 | pages = 1012–1025 | date = May 2015 | pmid = 25959774 | pmc = 4791538 | doi = 10.1016/j.cell.2015.04.004 }}{{Cite news | url=https://www.nytimes.com/2017/01/09/science/dna-tads.html?mcubz=1 | title=A Family's Shared Defect Sheds Light on the Human Genome| newspaper=The New York Times| date=2017-01-09| vauthors = Angier N }}{{cite journal | vauthors = Franke M, Ibrahim DM, Andrey G, Schwarzer W, Heinrich V, Schöpflin R, Kraft K, Kempfer R, Jerković I, Chan WL, Spielmann M, Timmermann B, Wittler L, Kurth I, Cambiaso P, Zuffardi O, Houge G, Lambie L, Brancati F, Pombo A, Vingron M, Spitz F, Mundlos S | display-authors = 6 | title = Formation of new chromatin domains determines pathogenicity of genomic duplications | language = En | journal = Nature | volume = 538 | issue = 7624 | pages = 265–269 | date = October 2016 | pmid = 27706140 | doi = 10.1038/nature19800 | hdl-access = free | s2cid = 4463482 | bibcode = 2016Natur.538..265F | hdl = 11858/00-001M-0000-002C-010A-3 }} 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),{{cite journal | vauthors = Hnisz D, Weintraub AS, Day DS, Valton AL, Bak RO, Li CH, Goldmann J, Lajoie BR, Fan ZP, Sigova AA, Reddy J, Borges-Rivera D, Lee TI, Jaenisch R, Porteus MH, Dekker J, Young RA | display-authors = 6 | title = Activation of proto-oncogenes by disruption of chromosome neighborhoods | journal = Science | volume = 351 | issue = 6280 | pages = 1454–1458 | date = March 2016 | pmid = 26940867 | pmc = 4884612 | doi = 10.1126/science.aad9024 | bibcode = 2016Sci...351.1454H }} gliomas,{{cite journal | vauthors = Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE | display-authors = 6 | title = Insulator dysfunction and oncogene activation in IDH mutant gliomas | journal = Nature | volume = 529 | issue = 7584 | pages = 110–114 | date = January 2016 | pmid = 26700815 | pmc = 4831574 | doi = 10.1038/nature16490 | bibcode = 2016Natur.529..110F }} and lung cancer.{{cite journal | vauthors = Weischenfeldt J, Dubash T, Drainas AP, Mardin BR, Chen Y, Stütz AM, Waszak SM, Bosco G, Halvorsen AR, Raeder B, Efthymiopoulos T, Erkek S, Siegl C, Brenner H, Brustugun OT, Dieter SM, Northcott PA, Petersen I, Pfister SM, Schneider M, Solberg SK, Thunissen E, Weichert W, Zichner T, Thomas R, Peifer M, Helland A, Ball CR, Jechlinger M, Sotillo R, Glimm H, Korbel JO | display-authors = 6 | title = Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking | journal = Nature Genetics | volume = 49 | issue = 1 | pages = 65–74 | date = January 2017 | pmid = 27869826 | pmc = 5791882 | doi = 10.1038/ng.3722 | author-link32 = Jan O. Korbel }}
Lamina-associated domains
File:Lamina associated domains, LAD.png
{{Main|Nuclear lamina}}
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.{{cite journal | author1 = Gonzalez-Sandoval A| author2 = Gasser SM| author-link2 = Susan M. Gasser | title = On TADs and LADs: Spatial Control Over Gene Expression | journal = Trends in Genetics | volume = 32 | issue = 8 | pages = 485–495 | date = August 2016 | pmid = 27312344 | doi = 10.1016/j.tig.2016.05.004 }} LADs consist mostly of transcriptionally silent chromatin, being enriched with trimethylated Lys27 on histone H3, (i.e. H3K27me3); which is a common posttranslational histone modification of heterochromatin.{{cite journal | vauthors = Li M, Liu GH, Izpisua Belmonte JC | title = Navigating the epigenetic landscape of pluripotent stem cells | journal = Nature Reviews. Molecular Cell Biology | volume = 13 | issue = 8 | pages = 524–535 | date = July 2012 | pmid = 22820889 | doi = 10.1038/nrm3393 | s2cid = 22524502 }} LADs have CTCF-binding sites at their periphery.
See also
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References
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External links
- [https://aidenlab.org/juicebox/ Juicebox]
- [http://docs.higlass.io HiGlass]
- [https://hipiler.lekschas.de HiPiler]
- [http://3dgenome.fsm.northwestern.edu/index.html 3D Genome Browser]
- [http://kobic.kr/3div/ 3DIV]
- [https://3dgnome.cent.uw.edu.pl 3D-GNOME]
- [http://dna.cs.miami.edu/TADKB/ TADKB]