Abstract
Genomes across a wide range of eukaryotic organisms fold into higher-order chromatin domains. Topologically associating domains (TADs) were originally discovered empirically in low-resolution Hi-C heat maps representing ensemble average interaction frequencies from millions of cells. Here, we discuss recent advances in high-resolution Hi-C, single-cell imaging experiments, and functional genetic studies, which provide an increasingly complex view of the genome’s hierarchical structure–function relationship. On the basis of these new findings, we update the definitions of distinct classes of chromatin domains according to emerging knowledge of their structural, mechanistic and functional properties.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).
Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012).
Hou, C., Li, L., Qin, Z. S. & Corces, V. G. Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains. Mol. Cell 48, 471–484 (2012).
Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472 (2012).
Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013).
Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).
Norton, H. K. et al. Detecting hierarchical genome folding with network modularity. Nat. Methods 15, 119–122 (2018).
Hsieh, T.-H.S. et al. Resolving the 3D landscape of transcription-linked mammalian chromatin folding. Preprint at bioRxiv https://doi.org/10.1101/638775 (2019).
Krietenstein, N. et al. Ultrastructural details of mammalian chromosome architecture. Preprint at bioRxiv https://doi.org/10.1101/639922 (2019).
Rowley, M. J. et al. Evolutionarily conserved principles predict 3D chromatin organization. Mol. Cell 67, 837–852.e837 (2017).
Phanstiel, D. H. et al. Static and dynamic DNA loops form AP-1-bound activation hubs during macrophage development. Mol. Cell 67, 1037–1048.e1036 (2017).
Phillips, J. E. & Corces, V. G. CTCF: master weaver of the genome. Cell 137, 1194–1211 (2009).
Tang, Z. et al. CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription. Cell 163, 1611–1627 (2015).
de Wit, E. et al. CTCF binding polarity determines chromatin looping. Mol. Cell 60, 676–684 (2015).
Guo, Y. et al. CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell 162, 900–910 (2015).
Sanborn, A. L. et al. Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes. Proc. Natl Acad. Sci. USA 112, E6456–E6465 (2015).
Nora, E. P. et al. Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization. Cell 169, 930–944.e922 (2017).
Nasmyth, K. Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis. Annu. Rev. Genet. 35, 673–745 (2001).
Riggs, A. D. DNA methylation and late replication probably aid cell memory, and type I DNA reeling could aid chromosome folding and enhancer function. Phil. Trans. R. Soc. Lond. B 326, 285–297 (1990).
Alipour, E. & Marko, J. F. Self-organization of domain structures by DNA-loop-extruding enzymes. Nucleic Acids Res. 40, 11202–11212 (2012).
Fudenberg, G. et al. Formation of chromosomal domains by loop extrusion. Cell Reports 15, 2038–2049 (2016).
Goloborodko, A., Marko, J. F. & Mirny, L. A. Chromosome compaction by active loop extrusion. Biophys. J. 110, 2162–2168 (2016).
Parelho, V. et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 132, 422–433 (2008).
Rubio, E. D. et al. CTCF physically links cohesin to chromatin. Proc. Natl Acad. Sci. USA 105, 8309–8314 (2008).
Stedman, W. et al. Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators. EMBO J. 27, 654–666 (2008).
Wendt, K. S. et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 451, 796–801 (2008).
Haarhuis, J. H. I. et al. The cohesin release factor WAPL restricts chromatin loop extension. Cell 169, 693–707.e614 (2017).
Rao, S. S. P. et al. Cohesin loss eliminates all loop domains. Cell 171, 305–320.e324 (2017).
Schwarzer, W. et al. Two independent modes of chromatin organization revealed by cohesin removal. Nature 551, 51–56 (2017).
Terakawa, T. et al. The condensin complex is a mechanochemical motor that translocates along DNA. Science 358, 672–676 (2017).
Ganji, M. et al. Real-time imaging of DNA loop extrusion by condensin. Science 360, 102–105 (2018).
Stigler, J., Çamdere, G. O., Koshland, D. E. & Greene, E. C. Single-molecule imaging reveals a collapsed conformational state for DNA-bound cohesin. Cell Rep. 15, 988–998 (2016).
Davidson, I. F. et al. Rapid movement and transcriptional re-localization of human cohesin on DNA. EMBO J. 35, 2671–2685 (2016).
Kanke, M., Tahara, E., Huis In’t Veld, P. J. & Nishiyama, T. Cohesin acetylation and Wapl-Pds5 oppositely regulate translocation of cohesin along DNA. EMBO J. 35, 2686–2698 (2016).
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).
Eagen, K. P., Aiden, E. L. & Kornberg, R. D. Polycomb-mediated chromatin loops revealed by a subkilobase-resolution chromatin interaction map. Proc. Natl Acad. Sci. USA 114, 8764–8769 (2017).
Bonev, B. et al. Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572.e524 (2017).
Kruse, K. et al. Transposable elements drive reorganisation of 3D chromatin during early embryogenesis. Preprint at bioRxiv https://doi.org/10.1101/523712 (2019).
Zhang, Y. et al. Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells. Nat. Genet. 51, 1380–1388 (2019).
Nagano, T. et al. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502, 59–64 (2013).
Flyamer, I. M. et al. Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544, 110–114 (2017).
Bintu, B. et al. Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362, eaau1783 (2018).
Symmons, O. et al. Functional and topological characteristics of mammalian regulatory domains. Genome Res. 24, 390–400 (2014).
Dowen, J. M. et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159, 374–387 (2014).
Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).
Lupiáñez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015).
Narendra, V. et al. CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. Science 347, 1017–1021 (2015).
van Bemmel, J. G. et al. The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist. Nat. Genet. 51, 1024–1034 (2019).
Kraft, K. et al. Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations. Nat. Cell Biol. 21, 305–310 (2019).
Laugsch, M. et al. Modeling the pathological long-range regulatory effects of human structural variation with patient-specific hiPSCs. Cell Stem Cell 24, 736–752.e712 (2019).
Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).
Despang, A. et al. Functional dissection of the Sox9–Kcnj2 locus identifies nonessential and instructive roles of TAD architecture. Nat. Genet. 51, 1263–1271 (2019).
Sun, J. H. et al. Disease-associated short tandem repeats co-localize with chromatin domain boundaries. Cell 175, 224–238.e15 (2018).
Franke, M. et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538, 265–269 (2016).
Norton, H. K. & Phillips-Cremins, J. E. Crossed wires: 3D genome misfolding in human disease. J. Cell Biol. 216, 3441–3452 (2017).
Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).
Fulco, C. P. et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat. Genet. 51, 1664–1669 (2019).
Mateo, L. J. et al. Visualizing DNA folding and RNA in embryos at single-cell resolution. Nature 568, 49–54 (2019).
Chen, H. et al. Dynamic interplay between enhancer-promoter topology and gene activity. Nat. Genet. 50, 1296–1303 (2018).
Alexander, J. M. et al. Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity. eLife 8, e41769 (2019).
Deng, W. et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell 149, 1233–1244 (2012).
Kim, J. H. et al. LADL: light-activated dynamic looping for endogenous gene expression control. Nat. Methods 16, 633–639 (2019).
Cuartero, S. et al. Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. Nat. Immunol. 19, 932–941 (2018).
Heinz, S. et al. Transcription elongation can affect genome 3D structure. Cell 174, 1522–1536.e1522 (2018).
Barutcu, A. R., Blencowe, B. J. & Rinn, J. L. Differential contribution of steady-state RNA and active transcription in chromatin organization. EMBO Rep. 20, e48068 (2019).
Williamson, I. et al. Developmentally regulated Shh expression is robust to TAD perturbations. Development 146, dev179523 (2019).
Paliou, C. et al. Preformed chromatin topology assists transcriptional robustness of Shh during limb development. Proc. Natl Acad. Sci. USA 116, 12390–12399 (2019).
Ghavi-Helm, Y. et al. Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression. Nat. Genet. 51, 1272–1282 (2019).
Symmons, O. et al. The Shh topological domain facilitates the action of remote enhancers by reducing the effects of genomic distances. Dev. Cell 39, 529–543 (2016).
Acknowledgements
We thank members of the 3D genome-folding community for helpful discussions. In particular, we gratefully acknowledge B. Ren for feedback on this work. J.E.P.-C. is supported as a New York Stem Cell Foundation—Robertson Investigator and an Alfred P. Sloan Foundation Fellow. This research was supported by The New York Stem Cell Foundation (J.E.P.-C.), the Alfred P. Sloan Foundation (J.E.P.-C.), the NIH Director’s New Innovator Award from the National Institute of Mental Health (1DP2MH11024701; J.E.P.-C.), a National Institute of Mental Health grant (1R011MH120269; J.E.P.-C.), a 4D Nucleome Common Fund grant (1U01HL12999801; J.E.P.-C), a joint NSF–NIGMS grant to support research at the interface of the biological and mathematical sciences (1562665; J.E.P.-C.), a Brain Research Foundation Fay Frank Seed Grant (J.E.P.-C.) and a National Science Foundation Graduate Research Fellowship under grant DGE-1321851 (J.A.B.).
Author information
Authors and Affiliations
Contributions
J.E.P.-C. and J.A.B. wrote the paper.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary Note
Rights and permissions
About this article
Cite this article
Beagan, J.A., Phillips-Cremins, J.E. On the existence and functionality of topologically associating domains. Nat Genet 52, 8–16 (2020). https://doi.org/10.1038/s41588-019-0561-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41588-019-0561-1
This article is cited by
-
Computational methods for analysing multiscale 3D genome organization
Nature Reviews Genetics (2024)
-
Human neuronal maturation comes of age: cellular mechanisms and species differences
Nature Reviews Neuroscience (2024)
-
In vitro reconstitution of chromatin domains shows a role for nucleosome positioning in 3D genome organization
Nature Genetics (2024)
-
GAGE-seq concurrently profiles multiscale 3D genome organization and gene expression in single cells
Nature Genetics (2024)
-
A comprehensive benchmarking with interpretation and operational guidance for the hierarchy of topologically associating domains
Nature Communications (2024)