Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data


Key Points

  • Mining increasingly comprehensive chromatin interaction maps for chromosomal domains and complete genomes requires novel computational methods and modelling tools.

  • Looping interactions between specific genomic elements — for example, gene promoters and regulatory elements — can be identified from chromatin interaction data by detecting interaction frequencies that are significantly higher than empirically estimated background levels. Looping interactions appear to be very abundant: most promoters interact with several other genomic elements.

  • Statistical analysis of Hi-C data identifies multiple scales of domain organization: larger (1–10 Mb) chromosomal compartments and smaller (<1 Mb) topologically associating domains.

  • Restraint-based modelling provides experiment-based models of genomes and genomic domains. Such models can be used as a starting point for targeted structure–function analyses.

  • Polymer simulations provide insights into the global chromatin organization that are consistent with statistical features of the interaction data, suggesting physical principles of chromatin folding.


How DNA is organized in three dimensions inside the cell nucleus and how this affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C), the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction data sets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyse chromatin interaction data.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Examples of 3C, 4C, 5C and Hi-C data sets.
Figure 2: Processes leading to close spatial proximity of loci.
Figure 3: Chromatin looping interactions and topologically associating domains.
Figure 4: Three-dimensional modelling of genomes and genomic domains.
Figure 5: Large-scale features of genome folding.


  1. 1

    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

  2. 2

    Nègre, N. et al. A cis-regulatory map of the Drosophila genome. Nature 471, 527–531 (2011).

    PubMed Central  PubMed  Google Scholar 

  3. 3

    Gerstein, M. B. et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775–1787 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  4. 4

    Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).

    CAS  PubMed  Google Scholar 

  5. 5

    van Steensel, B. & Dekker, J. Genomics tools for unraveling chromosome architecture. Nature Biotech. 28, 1089–1095 (2010).

    CAS  Google Scholar 

  6. 6

    Müller, I., Boyle, S., Singer, R. H., Bickmore, W. A. & Chubb, J. R. Stable morphology, but dynamic internal reorganisation, of interphase human chromosomes in living cells. PLoS ONE 5, e11560 (2010).

    PubMed Central  PubMed  Google Scholar 

  7. 7

    Boyle, S., Rodesch, M. J., Halvensleben, H. A., Jeddeloh, J. A. & Bickmore, W. A. Fluorescence in situ hybridization with high-complexity repeat-free oligonucleotide probes generated by massively parallel synthesis. Chromosome Res. 19, 901–909 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  8. 8

    Cremer, T. & Cremer, C. Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nature Rev. Genet. 2, 292–301 (2001).

    CAS  Google Scholar 

  9. 9

    Branco, M. R. & Pombo, A. Intermingling of chromosome territories in interphase suggests role in translocations and transcription-dependent associations. PLoS Biol. 4, e138 (2006).

    PubMed Central  PubMed  Google Scholar 

  10. 10

    Iborra, F. J., Pombo, A., Jackson, D. A. & Cook, P. R. Active RNA polymerases are localized within discrete transcription “factories' in human nuclei. J. Cell Sci. 109, 1427–1436 (1996).

    CAS  Google Scholar 

  11. 11

    Fraser, P. & Bickmore, W. Nuclear organization of the genome and the potential for gene regulation. Nature 447, 413–417 (2007).

    CAS  Google Scholar 

  12. 12

    Brown, J. M. et al. Association between active genes occurs at nuclear speckles and is modulated by chromatin environment. J. Cell Biol. 182, 1083–1097 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  13. 13

    Schoenfelder, S. et al. Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nature Genet. 42, 53–61 (2010).

    CAS  Google Scholar 

  14. 14

    Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).

    CAS  PubMed  Google Scholar 

  15. 15

    Németh, A. et al. Initial genomics of the human nucleolus. PLoS Genet. 6, e1000889 (2010).

    PubMed Central  PubMed  Google Scholar 

  16. 16

    van Koningsbruggen, S. et al. High-resolution whole-genome sequencing reveals that specific chromatin domains from most human chromosomes associate with nucleoli. Mol. Biol. Cell. 21, 3735–3748 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  17. 17

    Tolhuis, B. et al. Interactions among Polycomb domains are guided by chromosome architecture. PLoS Genet. 7, e1001343 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  18. 18

    Bantignies, F. et al. Polycomb-dependent regulatory contacts between distant Hox loci in Drosophila. Cell 144, 214–226 (2011).

    CAS  PubMed  Google Scholar 

  19. 19

    Pirrotta, V. & Li, H. B. A view of nuclear Polycomb bodies. Curr. Opin. Genet. Dev. 22, 101–109 (2012).

    CAS  Google Scholar 

  20. 20

    de Wit, E. & de Laat, W. A decade of 3C technologies: insights into nuclear organization. Genes Dev. 26, 11–24 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. 21

    Hakim, O. & Misteli, T. SnapShot: chromosome conformation capture. Cell 148, 1068–1068.e2 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  22. 22

    Ethier, S. D., Miura, H. & Dostie, J. Discovering genome regulation with 3C and 3C-related technologies. Biochim. Biophys. Acta. 1819, 401–410 (2012).

    CAS  Google Scholar 

  23. 23

    Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448–453 (2003).

    Google Scholar 

  24. 24

    Rippe, K. Making contacts on a nucleic acid polymer. Trends Biochem. Sci. 26, 733–740 (2001).

    CAS  Google Scholar 

  25. 25

    Fudenberg, G. & Mirny, L. A. Higher-order chromatin structure: bridging physics and biology. Curr. Opin. Genet. Dev. 22, 115–124 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  26. 26

    Chubb, J. R., Boyle, S., Perry, P. & Bickmore, W. A. Chromatin motion is constrained by association with nuclear compartments in human cells. Curr. Biol. 12, 439–445 (2002).

    CAS  Google Scholar 

  27. 27

    Marshall, W. F. et al. Interphase chromosomes undergo constrained diffusional motion in living cells. Curr. Biol. 7, 930–939 (1997).

    CAS  Google Scholar 

  28. 28

    Kalhor, R., Tjong, H., Jayathilaka, N., Alber, F. & Chen, L. Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nature Biotech. 30, 90–98 (2011). These authors apply simulations to analyse genome-wide chromatin interaction data to generate spatial models of nuclear organization that also capture the cell-to-cell variability in chromosome organization.

    Google Scholar 

  29. 29

    Tjong, H., Gong, K., Chen, L. & Alber, F. Physical tethering and volume exclusion determine higher-order genome organization in budding yeast. Genome Res. 22, 1295–1305 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  30. 30

    Miele, A. & Dekker, J. Long-range chromosomal interactions and gene regulation. Mol. BioSyst. 4, 1046–1057 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  31. 31

    Krivega, I. & Dean, A. Enhancer and promoter interactions—long distance calls. Curr. Opin. Genet. Dev. 22, 79–85 (2012).

    CAS  PubMed  Google Scholar 

  32. 32

    Tolhuis, B., Palstra, R. J., Splinter, E., Grosveld, F. & de Laat, W. Looping and interaction between hypersensitive sites in the active β-globin locus. Mol. Cell 10, 1453–1465 (2002).

    CAS  PubMed  Google Scholar 

  33. 33

    Ott, C. J. et al. Intronic enhancers coordinate epithelial-specific looping of the active CFTR locus. Proc. Natl Acad. Sci. USA 106, 19934–19939 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  34. 34

    Gheldof, N. et al. Cell-type-specific long-range looping interactions identify distant regulatory elements of the CFTR gene. Nucleic Acids Res. 38, 4235–4336 (2010).

    Google Scholar 

  35. 35

    Dekker, J. The 3 C's of chromosome conformation capture: controls, controls, controls. Nature Methods 3, 17–21 (2006).

    CAS  Google Scholar 

  36. 36

    Palstra, R. J. et al. The β-globin nuclear compartment in development and erythroid differentiation. Nature Genet. 35, 190–194 (2003).

    CAS  Google Scholar 

  37. 37

    Drissen, R. et al. The active spatial organization of the β-globin locus requires the transcription factor EKLF. Genes Dev. 18, 2485–2490 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  38. 38

    Vakoc, C. R. et al. Proximity among distant regulatory elements at the β-globin locus requires GATA-1 and FOG-1. Mol. Cell 17, 453–462 (2005).

    CAS  Google Scholar 

  39. 39

    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). In this work, the authors show that physical tethering of an enhancer to its target promoter can activate the gene, providing one of the first direct mechanistic insights into the role of chromatin looping in gene control.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. 40

    Vernimmen, D., De Gobbi, M., Sloane-Stanley, J. A., Wood, W. G. & Higgs, D. R. Long-range chromosomal interactions regulate the timing of the transition between poised and active gene expression. EMBO J. 26, 2041–2051 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  41. 41

    Spilianakis, C. G. & Flavell, R. A. Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nature Immunol. 5, 1017–1027 (2004).

    CAS  Google Scholar 

  42. 42

    Ahmadiyeh, N. et al. 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc. Natl Acad. Sci. USA 107, 9742–9746 (2010).

    CAS  PubMed  Google Scholar 

  43. 43

    Wright, J. B., Brown, S. J. & Cole, M. D. Upregulation of c-MYC in cis through a large chromatin loop linked to a cancer risk-associated single-nucleotide polymorphism in colorectal cancer cells. Mol. Cell. Biol. 30, 1411–1420 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  44. 44

    Majumder, P., Gomez, J. A., Chadwick, B. P. & Boss, J. M. The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. J. Exp. Med. 205, 785–798 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  45. 45

    Miele, A., Bystricky, K. & Dekker, J. Yeast silent mating type loci form heterochromatic clusters through silencer protein-dependent long-range interactions. PLoS Genet. 5, e1000478 (2009).

    PubMed Central  PubMed  Google Scholar 

  46. 46

    Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature 489, 109–113 (2012). In this paper, thousands of long-range interactions across 30 Mb in the human genome are discovered. This paper describes some of the statistical approaches that can be used to identify significant locus–locus interactions in comprehensive chromatin interaction data sets.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. 47

    Duan, Z. et al. A three-dimensional model of the yeast genome. Nature 465, 363–367 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  48. 48

    Simonis, M. et al. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nature Genet. 38, 1348–1354 (2006).

    CAS  Google Scholar 

  49. 49

    Hakim, O. et al. Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements. Genome Res. 21, 697–706 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 50

    Gibcus, J. H. & Dekker, J. The hierarchy of the 3D genome. Mol. Cell 49, 773–782 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  51. 51

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

    PubMed Central  PubMed  Google Scholar 

  52. 52

    Handoko, L. et al. CTCF-mediated functional chromatin interactome in pluripotent cells. Nature Genet. 43, 630–638 (2011).

    CAS  Google Scholar 

  53. 53

    Kleinjan, D. A. & van Heyningen, V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am. J. Hum. Genet. 76, 8–32 (2005).

    CAS  Google Scholar 

  54. 54

    Gerstein, M. B. et al. Architecture of the human regulatory network derived from ENCODE data. Nature 489, 91–100 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  55. 55

    Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  56. 56

    Shen, Y. et al. A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116–120 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  57. 57

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

    CAS  PubMed Central  PubMed  Google Scholar 

  58. 58

    Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012). This paper describes the discovery of TADs using 5C and shows that TAD boundaries are independent of chromatin modification but are defined by genetic cis -elements.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. 59

    Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012). This paper describes the discovery of TADs and discusses a computational strategy to identify TAD boundaries using Hi-C data sets.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. 60

    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 Central  PubMed  Google Scholar 

  61. 61

    Gaszner, M. & Felsenfeld, G. Insulators: exploiting transcriptional and epigenetic mechanisms. Nature Rev. Genet. 7, 703–713 (2006).

    CAS  Google Scholar 

  62. 62

    Caron, H. et al. The human transcriptome map: clustering of highly expressed genes in chromosomal domains. Science 291, 1289–1292 (2001).

    CAS  Google Scholar 

  63. 63

    Spellman, P. T. & Rubin, G. M. Evidence for large domains of similarly expressed genes in the Drosophila genome. J. Biol. 1, 5 (2002).

    PubMed Central  PubMed  Google Scholar 

  64. 64

    Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009). This work describes development of the Hi-C method and how polymer simulations can be used to analyse chromatin interaction data. This work also described the fractal globule state of chromatin at the 1–10 Mb scale.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. 65

    Marti-Renom, M. A. & Mirny, L. A. Bridging the resolution gap in structural modeling of 3D genome organization. PLoS Comput. Biol. 7, e1002125 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  66. 66

    Baù, D. & Marti-Renom, M. A. Structure determination of genomic domains by satisfaction of spatial restraints. Chromosome Res. 19, 25–35 (2011).

    Google Scholar 

  67. 67

    Jhunjhunwala, S. et al. The 3D structure of the immunoglobulin heavy-chain locus: implications for long-range genomic interactions. Cell 133, 265–279 (2008). This worked combined FISH data and polymer modelling to obtained spatial models for the immunoglobulin heavy-chain locus.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. 68

    Fraser, J. et al. Chromatin conformation signatures of cellular differentiation. Genome Biol. 10, R37 (2009).

    PubMed Central  PubMed  Google Scholar 

  69. 69

    Russel, D. et al. Putting the pieces together: integrative modeling platform software for structure determination of macromolecular assemblies. PLoS Biol. 10, e1001244 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  70. 70

    Sanyal, A., Baù, D., Martí-Renom, M. A. & Dekker, J. Chromatin globules: a common motif of higher order chromosome structure? Curr. Opin. Cell Biol. 23, 325–331 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  71. 71

    Baù, D. et al. The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules. Nature Struct. Mol. Biol. 18, 107–114 (2011). These authors describe a restraint-based modelling approach to use chromatin interaction data to derive spatial models of chromatin domains.

    Google Scholar 

  72. 72

    Umbarger, M. A. et al. The three-dimensional architecture of a bacterial genome and its alteration by genetic perturbation. Mol. Cell 44, 252–264 (2011).

    CAS  Google Scholar 

  73. 73

    Ebersbach, G., Briegel, A., Jensen, G. J. & Jacobs-Wagner, C. A self-associating protein critical for chromosome attachment, division, and polar organization in caulobacter. Cell 134, 956–968 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  74. 74

    Bowman, G. R. et al. A polymeric protein anchors the chromosomal origin/ParB complex at a bacterial cell pole. Cell 134, 945–955 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  75. 75

    Tanizawa, H. et al. Mapping of long-range associations throughout the fission yeast genome reveals global genome organization linked to transcriptional regulation. Nucleic Acids Res. 38, 8164–8177 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  76. 76

    Hu, M. et al. Bayesian inference of spatial organizations of chromosomes. PLoS Comput. Biol. 9, e1002893 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  77. 77

    Jin, Q. W., Fuchs, J. & Loidl, J. Centromere clustering is a major determinant of yeast interphase nuclear organization. J. Cell Sci. 113, 1903–1912 (2000).

    CAS  Google Scholar 

  78. 78

    Taddei, A. & Gasser, S. M. Structure and function in the budding yeast nucleus. Genetics 192, 107–129 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  79. 79

    van den Engh, G., Sachs, R. & Trask, B. J. Estimating genomic distance from DNA sequence location in cell nuclei by a random walk model. Science 257, 1410 (1992).

    CAS  Google Scholar 

  80. 80

    McManus, J. et al. Unusual chromosome structure of fission yeast DNA in mouse cells. J. Cell Sci. 107, 469–486 (1994).

    CAS  Google Scholar 

  81. 81

    Hahnfeldt, P. et al. Polymer models for interphase chromosomes. Proc. Natl Acad. Sci. USA 90, 7854–7858 (1993).

    CAS  Google Scholar 

  82. 82

    Marko, J. F. & Siggia, E. D. Polymer models of meiotic and mitotic chromosomes. Mol. Biol. Cell 8, 2217–2231 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 83

    Sachs, R. K. et al. A random-walk/giant-loop model for interphase chromosomes. Proc. Natl Acad. Sci. USA 92, 2710–2714 (1995).

    CAS  Google Scholar 

  84. 84

    Sikorav, J. L. & Jannink, G. Kinetics of chromosome condensation in the presence of topoisomerases: a phantom chain model. Biophys. J. 66, 827 (1994).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 85

    Grosberg, A., Rabin, Y., Havlin, S. & Neer, A. Crumpled globule model of the three-dimensional structure of DNA. Europhys. Lett. 23, 373 (1993).

    CAS  Google Scholar 

  86. 86

    Vologodskii, A. V., Levene, S. D., Klenin, K. V., Frank-Kamenetskii, M. & Cozzarelli, N. R. Conformational and thermodynamic properties of supercoiled DNA. J. Mol. Biol. 227, 1224–1243 (1992).

    CAS  Google Scholar 

  87. 87

    Bohn, M. & Heermann, D. W. Repulsive forces between looping chromosomes induce entropy-driven segregation. PLoS ONE 6, e14428 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  88. 88

    Dorier, J. & Stasiak, A. The role of transcription factories-mediated interchromosomal contacts in the organization of nuclear architecture. Nucleic Acids Res. 38, 7410–7421 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  89. 89

    Vettorel, T., Grosberg, A. Y. & Kremer, K. Statistics of polymer rings in the melt: a numerical simulation study. Phys. Biol. 6, 025013 (2009).

    Google Scholar 

  90. 90

    Rosa, A. & Everaers, R. Structure and dynamics of interphase chromosomes. PLoS Comput. Biol. 4, e1000153 (2008).

    PubMed Central  PubMed  Google Scholar 

  91. 91

    Cook, P. R. & Marenduzzo, D. Entropic organization of interphase chromosomes. J. Cell Biol. 186, 825–834 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  92. 92

    Jerabek, H. & Heermann, D. W. Expression-dependent folding of interphase chromatin. PLoS ONE 7, e37525 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. 93

    Bohn, M. & Heermann, D. W. Diffusion-driven looping provides a consistent framework for chromatin organization. PLoS ONE 5, e12218 (2010).

    PubMed Central  PubMed  Google Scholar 

  94. 94

    Mateos-Langerak, J. et al. Spatially confined folding of chromatin in the interphase nucleus. Proc. Natl Acad. Sci. USA 106, 3812–3817 (2009).

    CAS  Google Scholar 

  95. 95

    Barbieri, M. et al. Complexity of chromatin folding is captured by the strings and binders switch model. Proc. Natl Acad. Sci. 109, 16173–16178 (2012).

    CAS  Google Scholar 

  96. 96

    Rosa, A., Becker, N. B. & Everaers, R. Looping probabilities in model. Interphase chromosomes. Biophys. J. 98, 2410–2419 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  97. 97

    Grosberg, A. Y., Nechaev, S. K. & Shakhnovich, E. I. The role of topological constraints in the kinetics of collapse of macromolecules. J. Physique 49, 2095–2100 (1988).

    CAS  Google Scholar 

  98. 98

    Mirny, L. A. The fractal globule as a model of chromatin architecture in the cell. Chromosome Res. 19, 37–51 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  99. 99

    Rapkin, L. M., Anchel, D. R. P., Li, R. & Bazett-Jones, D. P. A view of the chromatin landscape. Micron 43, 150–158 (2012).

    CAS  Google Scholar 

  100. 100

    Belmont, A. S. et al. Insights into interphase large-scale chromatin structure from analysis of engineered chromosome regions. Cold Spring Harbor Symp. Quant. Biol. 75, 453–460 (2011).

    Google Scholar 

  101. 101

    Towbin, B. D. et al. Step-wise methylation of histone h3k9 positions heterochromatin at the nuclear periphery. Cell 150, 934–947 (2012).

    CAS  PubMed  Google Scholar 

  102. 102

    Emanuel, M., Radja, N. H., Henriksson, A. & Schiessel, H. The physics behind the larger scale organization of DNA in eukaryotes. Phys. Biol. 6, 025008 (2009).

    Google Scholar 

  103. 103

    Shopland, L. S. et al. Folding and organization of a contiguous chromosome region according to the gene distribution pattern in primary genomic sequence. J. Cell Biol. 174, 27–38 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  104. 104

    Rubinstein, M. & Colby, R. H. Polymer Physics (Oxford Univ. Press, 2003).

    Google Scholar 

  105. 105

    Würtele, H. & Chartrand, P. Genome-wide scanning of HoxB1-associated loci in mouse ES cells using an open-ended chromosome conformation capture methodology. Chromosome Res. 14, 477–495 (2006).

    Google Scholar 

  106. 106

    Zhao, Z. et al. Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nature Genet. 38, 1341–1347 (2006).

    CAS  Google Scholar 

  107. 107

    Dostie, J. et al. Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res. 16, 1299–1309 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  108. 108

    Lajoie, B. R., van Berkum, N. L., Sanyal, A. & Dekker, J. My5C: web tools for chromosome conformation capture studies. Nature Methods 6, 690–691 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  109. 109

    Horike, S., Cai, S., Miyano, M., Cheng, J. F. & Kohwi-Shigematsu, T. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nature Genet. 37, 31–40 (2005).

    CAS  Google Scholar 

  110. 110

    Fullwood, M. J. et al. An oestrogen-receptor-α-bound human chromatin interactome. Nature 462, 58–64 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  111. 111

    Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  112. 112

    Imakaev, M. et al. Iterative correction of Hi-C data reveals hallmarks of chromosome organization. Nature Methods 9, 999–1003 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  113. 113

    Mouse ENCODE Consortium. An encyclopedia of mouse DNA elements (Mouse ENCODE). Genome Biol. 13, 418 (2012).

Download references


We are grateful to all the members of our groups for many discussions about three-dimensional genomics. Supported by grants from the US National Institutes of Health (NIH), US National Human Genome Research Institute (HG003143 and HG003143-06S1) and a W.M. Keck Foundation distinguished young scholar in medical research grant to J.D.; financial support from the Spanish Ministerio de Ciencia e Innovación (BFU2010-19310/BMC), the Human Frontiers Science Program (RGP0044/2011) and the BLUEPRINT project (EU FP7 grant agreement 282510) to M.A.M.-R.; and a grant from the NIH National Cancer Institute (Physical Sciences–Oncology Center at Massachusetts Institutes of Technology Grant U54CA143874) to L.A.M.

Author information



Corresponding author

Correspondence to Job Dekker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides


Restraint-based modelling

A computational method to model the three-dimensional structure of an object represented by points and restraints between them.

Chromosome territories

Each territory is the domain of a nucleus occupied by a chromosome.

Polycomb bodies

Discrete nuclear foci containing Polycomb proteins and their silenced target genes. Polycomb bodies have been observed in Drosophila melanogaster and human cells by imaging and in situ hybridization.

Nuclear lamina

A scaffold of lamin proteins predominantly found in the nuclear periphery associated with the inner surface of the nuclear membrane.

Transcription factory

A nuclear compartments in which active transcription takes place; it has a high concentration of RNA polymerase II.


Forces (or scoring functions) that restrict the movement of objects (or points) that they apply to. Often used synonymously with 'restraint'.

Locus control region

(LCR). A cis-acting element that organizes a gene cluster into an active chromatin domain and enhances transcription in a tissue-specific manner.


A highly conserved zinc finger protein that influences chromatin organization and architecture and is implicated in diverse regulatory functions, including transcriptional activation, repression and insulation.

X-chromosome inactivation centre

A genetically defined locus of several megabases on the X chromosome of mammals that is required to initiate transcriptional repression along a single X chromosome in female cells.

Boundary elements

DNA elements that lie between two gene-controlling elements, such as a promoter and an enhancer, or between two large chromosomal domains, preventing their communication or interaction. The function of boundary elements is usually mediated by the binding of specific factors.


Forces (or scoring functions) that maintain the objects (or points) to which they apply at their position of equilibrium.

Rabl configuration

A pattern of nuclear organization in which centromeres of all chromosomes are spatially clustered and their arms run in parallel. This organization has been proposed to be a passive consequence of chromosome segregation but can also be actively maintained by mechanisms that cluster centromeres.

Fractal globule

A dense, non-equilibrium polymer state, which emerges as a result of a polymer condensation. In this state, the polymer is unknotted and each region of the chain is locally compact, allowing easy opening and closing of chromosomal regions.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dekker, J., Marti-Renom, M. & Mirny, L. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 14, 390–403 (2013).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing