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On the existence and functionality of topologically associating domains

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.

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Fig. 1: The structural features of topologically associating domains.
Fig. 2: Chromatin domains and their boundaries are present in single cells.
Fig. 3: Evidence for and against TADs as a critical functional intermediary in the regulation of genes by developmentally active enhancers.

References

  1. 1.

    Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472 (2012).

    CAS  PubMed  Google Scholar 

  5. 5.

    Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Norton, H. K. et al. Detecting hierarchical genome folding with network modularity. Nat. Methods 15, 119–122 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    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).

  9. 9.

    Krietenstein, N. et al. Ultrastructural details of mammalian chromosome architecture. Preprint at bioRxiv https://doi.org/10.1101/639922 (2019).

  10. 10.

    Rowley, M. J. et al. Evolutionarily conserved principles predict 3D chromatin organization. Mol. Cell 67, 837–852.e837 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Phillips, J. E. & Corces, V. G. CTCF: master weaver of the genome. Cell 137, 1194–1211 (2009).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Tang, Z. et al. CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription. Cell 163, 1611–1627 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    de Wit, E. et al. CTCF binding polarity determines chromatin looping. Mol. Cell 60, 676–684 (2015).

    PubMed  Google Scholar 

  15. 15.

    Guo, Y. et al. CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell 162, 900–910 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    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).

    CAS  PubMed  Google Scholar 

  17. 17.

    Nora, E. P. et al. Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization. Cell 169, 930–944.e922 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Nasmyth, K. Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis. Annu. Rev. Genet. 35, 673–745 (2001).

    CAS  PubMed  Google Scholar 

  19. 19.

    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).

    CAS  Google Scholar 

  20. 20.

    Alipour, E. & Marko, J. F. Self-organization of domain structures by DNA-loop-extruding enzymes. Nucleic Acids Res. 40, 11202–11212 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Fudenberg, G. et al. Formation of chromosomal domains by loop extrusion. Cell Reports 15, 2038–2049 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Goloborodko, A., Marko, J. F. & Mirny, L. A. Chromosome compaction by active loop extrusion. Biophys. J. 110, 2162–2168 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Parelho, V. et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 132, 422–433 (2008).

    CAS  PubMed  Google Scholar 

  24. 24.

    Rubio, E. D. et al. CTCF physically links cohesin to chromatin. Proc. Natl Acad. Sci. USA 105, 8309–8314 (2008).

    CAS  PubMed  Google Scholar 

  25. 25.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Wendt, K. S. et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 451, 796–801 (2008).

    CAS  PubMed  Google Scholar 

  27. 27.

    Haarhuis, J. H. I. et al. The cohesin release factor WAPL restricts chromatin loop extension. Cell 169, 693–707.e614 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Rao, S. S. P. et al. Cohesin loss eliminates all loop domains. Cell 171, 305–320.e324 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Schwarzer, W. et al. Two independent modes of chromatin organization revealed by cohesin removal. Nature 551, 51–56 (2017).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Terakawa, T. et al. The condensin complex is a mechanochemical motor that translocates along DNA. Science 358, 672–676 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Ganji, M. et al. Real-time imaging of DNA loop extrusion by condensin. Science 360, 102–105 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Davidson, I. F. et al. Rapid movement and transcriptional re-localization of human cohesin on DNA. EMBO J. 35, 2671–2685 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    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).

    CAS  PubMed  Google Scholar 

  37. 37.

    Bonev, B. et al. Multiscale 3D genome rewiring during mouse neural development. Cell 171, 557–572.e524 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kruse, K. et al. Transposable elements drive reorganisation of 3D chromatin during early embryogenesis. Preprint at bioRxiv https://doi.org/10.1101/523712 (2019).

  39. 39.

    Zhang, Y. et al. Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells. Nat. Genet. 51, 1380–1388 (2019).

    CAS  PubMed  Google Scholar 

  40. 40.

    Nagano, T. et al. Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502, 59–64 (2013).

    CAS  PubMed  Google Scholar 

  41. 41.

    Flyamer, I. M. et al. Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544, 110–114 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Bintu, B. et al. Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362, eaau1783 (2018).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Symmons, O. et al. Functional and topological characteristics of mammalian regulatory domains. Genome Res. 24, 390–400 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Dowen, J. M. et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell 159, 374–387 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Lupiáñez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Narendra, V. et al. CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. Science 347, 1017–1021 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    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).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kraft, K. et al. Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations. Nat. Cell Biol. 21, 305–310 (2019).

    CAS  PubMed  Google Scholar 

  50. 50.

    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).

    CAS  PubMed  Google Scholar 

  51. 51.

    Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).

    CAS  PubMed  Google Scholar 

  52. 52.

    Despang, A. et al. Functional dissection of the Sox9Kcnj2 locus identifies nonessential and instructive roles of TAD architecture. Nat. Genet. 51, 1263–1271 (2019).

    CAS  PubMed  Google Scholar 

  53. 53.

    Sun, J. H. et al. Disease-associated short tandem repeats co-localize with chromatin domain boundaries. Cell 175, 224–238.e15 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Franke, M. et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538, 265–269 (2016).

    CAS  PubMed  Google Scholar 

  55. 55.

    Norton, H. K. & Phillips-Cremins, J. E. Crossed wires: 3D genome misfolding in human disease. J. Cell Biol. 216, 3441–3452 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Fulco, C. P. et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat. Genet. 51, 1664–1669 (2019).

    CAS  PubMed  Google Scholar 

  58. 58.

    Mateo, L. J. et al. Visualizing DNA folding and RNA in embryos at single-cell resolution. Nature 568, 49–54 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Chen, H. et al. Dynamic interplay between enhancer-promoter topology and gene activity. Nat. Genet. 50, 1296–1303 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Alexander, J. M. et al. Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity. eLife 8, e41769 (2019).

    PubMed  PubMed Central  Google Scholar 

  61. 61.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Kim, J. H. et al. LADL: light-activated dynamic looping for endogenous gene expression control. Nat. Methods 16, 633–639 (2019).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Cuartero, S. et al. Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. Nat. Immunol. 19, 932–941 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Heinz, S. et al. Transcription elongation can affect genome 3D structure. Cell 174, 1522–1536.e1522 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Williamson, I. et al. Developmentally regulated Shh expression is robust to TAD perturbations. Development 146, dev179523 (2019).

    CAS  PubMed  Google Scholar 

  67. 67.

    Paliou, C. et al. Preformed chromatin topology assists transcriptional robustness of Shh during limb development. Proc. Natl Acad. Sci. USA 116, 12390–12399 (2019).

    CAS  PubMed  Google Scholar 

  68. 68.

    Ghavi-Helm, Y. et al. Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression. Nat. Genet. 51, 1272–1282 (2019).

    CAS  PubMed  Google Scholar 

  69. 69.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

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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.).

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J.E.P.-C. and J.A.B. wrote the paper.

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Correspondence to Jennifer E. Phillips-Cremins.

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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

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