Chromosome crosstalk in three dimensions


The genome forms extensive and dynamic physical interactions with itself in the form of chromosome loops and bridges, thus exploring the three-dimensional space of the nucleus. It is now possible to examine these interactions at the molecular level, and we have gained glimpses of their functional implications. Chromosomal interactions can contribute to the silencing and activation of genes within the three-dimensional context of the nuclear architecture. Technical advances in detecting these interactions contribute to our understanding of the functional organization of the genome, as well as its adaptive plasticity in response to environmental changes during development and disease.

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Figure 1: Structural constraints of DNA/chromatin loop formation.
Figure 2: Intrachromosomal and interchromosomal interactions in relation to chromosome territories.
Figure 3: Radial organization of chromosome territories within the nucleus regulates opportunities for chromatin crosstalk.
Figure 4: Genetic background may influence the expressivity of the genome through chromosome loops and/or bridges.


  1. 1

    Wilson, E. The Cell in Development and Heredity (Macmillan, 1928).

    Google Scholar 

  2. 2

    Duncan, I. W. Transvection effects in Drosophila . Annu. Rev. Genet. 36, 521–556 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Cook, P. R. The organization of replication and transcription. Science 284, 1790–1795 (1999).

    CAS  Article  Google Scholar 

  4. 4

    Misteli, T. Nuclear order out of chaos. Nature 456, 333–334 (2008).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Kaiser, T. E., Intine, R. V. & Dundr, M. De novo formation of a subnuclear body. Science 322, 1713–1717 (2008).

    ADS  CAS  Article  Google Scholar 

  6. 6

    McStay, B. & Grummt, I. The epigenetics of rRNA genes: from molecular to chromosome biology. Annu. Rev. Cell Dev. Biol. 24, 131–157 (2008).

    CAS  Article  Google Scholar 

  7. 7

    Lanctot, C., Cheutin, T., Cremer, M., Cavalli, G. & Cremer, T. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nature Rev. Genet. 8, 104–115 (2007).

    CAS  Article  Google Scholar 

  8. 8

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

    ADS  CAS  Article  Google Scholar 

  9. 9

    Osborne, C. S. et al. Active genes dynamically colocalize to shared sites of ongoing transcription. Nature Genet. 36, 1065–1071 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Jackson, D. A., Hassan, A. B., Errington, R. J. & Cook, P. R. Visualization of focal sites of transcription within human nuclei. EMBO J. 12, 1059–1065 (1993).

    CAS  Article  Google Scholar 

  11. 11

    Faro-Trindade, I. & Cook, P. R. Transcription factories: structures conserved during differentiation and evolution. Biochem. Soc. Trans. 34, 1133–1137 (2006).

    CAS  Article  Google Scholar 

  12. 12

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

    ADS  CAS  Article  Google Scholar 

  13. 13

    Hassan, A. B. & Cook, P. R. Visualization of replication sites in unfixed human cells. J. Cell Sci. 105, 541–550 (1993).

    PubMed  Google Scholar 

  14. 14

    Chakalova, L., Debrand, E., Mitchell, J. A., Osborne, C. S. & Fraser, P. Replication and transcription: shaping the landscape of the genome. Nature Rev. Genet. 6, 669–677 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Göndör, A. & Ohlsson, R. Replication timing and epigenetic reprogramming of gene expression: a two-way relationship? Nature Rev. Genet. 10, 269–276 (2009).

    Article  Google Scholar 

  16. 16

    Soutoglou, E. & Misteli, T. Mobility and immobility of chromatin in transcription and genome stability. Curr. Opin. Genet. Dev. 17, 435–442 (2007).

    CAS  Article  Google Scholar 

  17. 17

    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  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

    Li, Q., Barkess, G. & Qian, H. Chromatin looping and the probability of transcription. Trends Genet. 22, 197–202 (2006).

    Article  Google Scholar 

  20. 20

    Ishihara, K., Oshimura, M. & Nakao, M. CTCF-dependent chromatin insulator is linked to epigenetic remodeling. Mol. Cell 23, 733–742 (2006).

    CAS  Article  Google Scholar 

  21. 21

    Cremer, T. & Cremer, C. Rise, fall and resurrection of chromosome territories: a historical perspective. Part II. Fall and resurrection of chromosome territories during the 1950s to 1980s. Part III. Chromosome territories and the functional nuclear architecture: experiments and models from the 1990s to the present. Eur. J. Histochem. 50, 223–272 (2006).

    CAS  PubMed  Google Scholar 

  22. 22

    Hu, Q. et al. Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules. Proc. Natl Acad. Sci. USA 105, 19199–19204 (2008). This report demonstrates that chromatin crosstalk involves directed rapid movement of interacting loci and that this process is frequently accompanied by reorganization of the chromosome territories.

    ADS  CAS  Article  Google Scholar 

  23. 23

    Apostolou, E. & Thanos, D. Virus infection induces NF-κB-dependent interchromosomal associations mediating monoallelic IFN-β gene expression. Cell 134, 85–96 (2008). This report shows that the organization of the IFNB enhanceosome requires the juxtaposition of one or more sequences from other chromosomes that contain NF-κB-bound Alu repeats.

    CAS  Article  Google Scholar 

  24. 24

    Walter, J., Hutter, B., Khare, T. & Paulsen, M. Repetitive elements in imprinted genes. Cytogenet. Genome Res. 113, 109–115 (2006).

    CAS  Article  Google Scholar 

  25. 25

    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  Article  Google Scholar 

  26. 26

    Bartlett, J. et al. Specialized transcription factories. Biochem. Soc. Symp. 73, 67–75 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Xu, M. & Cook, P. R. Similar active genes cluster in specialized transcription factories. J. Cell Biol. 181, 615–623 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Cai, S., Lee, C. C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nature Genet. 38, 1278–1288 (2006).

    CAS  Article  Google Scholar 

  29. 29

    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  Article  Google Scholar 

  30. 30

    Tsytsykova, A. V. et al. Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers. Proc. Natl Acad. Sci. USA 104, 16850–16855 (2007).

    ADS  CAS  Article  Google Scholar 

  31. 31

    Deschenes, J., Bourdeau, V., White, J. H. & Mader, S. Regulation of GREB1 transcription by estrogen receptor α through a multipartite enhancer spread over 20 kb of upstream flanking sequences. J. Biol. Chem. 282, 17335–17339 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Nemeth, A., Guibert, S., Tiwari, V. K., Ohlsson, R. & Langst, G. Epigenetic regulation of TTF-I-mediated promoter–terminator interactions of rRNA genes. EMBO J. 27, 1255–1265 (2008).

    CAS  Article  Google Scholar 

  33. 33

    Bushey, A. M., Dorman, E. R. & Corces, V. G. Chromatin insulators: regulatory mechanisms and epigenetic inheritance. Mol. Cell 32, 1–9 (2008).

    CAS  Article  Google Scholar 

  34. 34

    Ohlsson, R., Renkawitz, R. & Lobanenkov, V. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 17, 520–527 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Kim, J. H. et al. Human gamma-satellite DNA maintains open chromatin structure and protects a transgene from epigenetic silencing. Genome Res. 19, 533–544 (2009).

    CAS  Article  Google Scholar 

  36. 36

    Kim, T. H. et al. Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128, 1231–1245 (2007).

    CAS  Article  Google Scholar 

  37. 37

    Yusufzai, T. M., Tagami, H., Nakatani, Y. & Felsenfeld, G. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol. Cell 13, 291–298 (2004).

    CAS  Article  Google Scholar 

  38. 38

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

    CAS  Article  Google Scholar 

  39. 39

    Splinter, E. et al. CTCF mediates long-range chromatin looping and local histone modification in the β-globin locus. Genes Dev. 20, 2349–2354 (2006).

    CAS  Article  Google Scholar 

  40. 40

    Kurukuti, S. et al. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2 . Proc. Natl Acad. Sci. USA 103, 10684–10689 (2006).

    ADS  CAS  Article  Google Scholar 

  41. 41

    Li, T. et al. CTCF regulates allelic expression of Igf2 by orchestrating a promoter-polycomb repressive complex 2 intrachromosomal loop. Mol. Cell. Biol. 28, 6473–6482 (2008).

    CAS  Article  Google Scholar 

  42. 42

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

    CAS  Article  Google Scholar 

  43. 43

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

    ADS  CAS  Article  Google Scholar 

  44. 44

    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  Article  Google Scholar 

  45. 45

    Hadjur, S. et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460, 410–413 (2009).

    ADS  CAS  Article  Google Scholar 

  46. 46

    Göndör, A. & Ohlsson, R. Chromatin insulators and cohesins. EMBO Rep. 9, 327–329 (2008).

    Article  Google Scholar 

  47. 47

    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  Article  Google Scholar 

  48. 48

    Ling, J. Q. et al. CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1 . Science 312, 269–272 (2006).

    ADS  CAS  Article  Google Scholar 

  49. 49

    Masui, O. & Heard, E. RNA and protein actors in X-chromosome inactivation. Cold Spring Harb. Symp. Quant. Biol. 71, 419–428 (2006).

    CAS  Article  Google Scholar 

  50. 50

    Xu, N., Donohoe, M. E., Silva, S. S. & Lee, J. T. Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein. Nature Genet. 39, 1390–1396 (2007).

    CAS  Article  Google Scholar 

  51. 51

    Chaumeil, J., Le Baccon, P., Wutz, A. & Heard, E. A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev. 20, 2223–2237 (2006).

    CAS  Article  Google Scholar 

  52. 52

    Zhao, J., Sun, B. K., Erwin, J. A., Song, J. J. & Lee, J. T. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322, 750–756 (2008).

    ADS  CAS  Article  Google Scholar 

  53. 53

    Lanzuolo, C., Roure, V., Dekker, J., Bantignies, F. & Orlando, V. Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex. Nature Cell Biol. 9, 1167–1174 (2007).

    CAS  Article  Google Scholar 

  54. 54

    Tiwari, V. K. et al. PcG proteins, DNA methylation, and gene repression by chromatin looping. PLoS Biol. 6, e306 (2008).

    Article  Google Scholar 

  55. 55

    Garrick, D. et al. The role of the polycomb complex in silencing α-globin gene expression in nonerythroid cells. Blood 112, 3889–3899 (2008).

    CAS  Article  Google Scholar 

  56. 56

    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  Article  Google Scholar 

  57. 57

    Solovei, I. et al. Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution. Cell 137, 356–368 (2009). This report demonstrates that, contrary to expectations, the nuclear architecture in the rod cells of the eye can undergo dramatic reorganization to adapt to a new function associated with nocturnal mammals.

    CAS  Article  Google Scholar 

  58. 58

    Richter, K., Nessling, M. & Lichter, P. Macromolecular crowding and its potential impact on nuclear function. Biochim. Biophys. Acta 1783, 2100–2107 (2008).

    CAS  Article  Google Scholar 

  59. 59

    Shimi, T. et al. The A- and B-type nuclear lamin networks: microdomains involved in chromatin organization and transcription. Genes Dev. 22, 3409–3421 (2008).

    CAS  Article  Google Scholar 

  60. 60

    Mehta, I. S., Elcock, L. S., Amira, M., Kill, I. R. & Bridger, J. M. Nuclear motors and nuclear structures containing A-type lamins and emerin: is there a functional link? Biochem. Soc. Trans. 36, 1384–1388 (2008).

    CAS  Article  Google Scholar 

  61. 61

    Spilianakis, C. G., Lalioti, M. D., Town, T., Lee, G. R. & Flavell, R. A. Interchromosomal associations between alternatively expressed loci. Nature 435, 637–645 (2005).

    ADS  CAS  Article  Google Scholar 

  62. 62

    Aladjem, M. I. Replication in context: dynamic regulation of DNA replication patterns in metazoans. Nature Rev. Genet. 8, 588–600 (2007).

    CAS  Article  Google Scholar 

  63. 63

    Hiratani, I. et al. Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol. 6, e245 (2008).

    Article  Google Scholar 

  64. 64

    Unneberg, P. & Claverie, J. M. Tentative mapping of transcription-induced interchromosomal interaction using chimeric EST & mRNA data. PLoS ONE 2, e254 (2007).

    ADS  Article  Google Scholar 

  65. 65

    Ohlsson, R. Widespread monoallelic expression. Science 318, 1077–1078 (2007).

    CAS  Article  Google Scholar 

  66. 66

    Parada, L. A., McQueen, P. G. & Misteli, T. Tissue-specific spatial organization of genomes. Genome Biol. 5, R44 (2004).

    Article  Google Scholar 

  67. 67

    Ghoussaini, M. et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl Cancer Inst. 100, 962–966 (2008).

    CAS  Article  Google Scholar 

  68. 68

    Steidl, U. et al. A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J. Clin. Invest. 117, 2611–2620 (2007).

    CAS  Article  Google Scholar 

  69. 69

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

    Article  Google Scholar 

  70. 70

    Osborne, C. S. et al. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh . PLoS Biol. 5, e192 (2007).

    Article  Google Scholar 

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We most gratefully acknowledge I. Solovei, B. Joffe, P. Cook, G. Klein and E. Heard for discussions. This work was supported by the Swedish Science Research Council, the Swedish Cancer Research Foundation, the Swedish Pediatric Cancer Foundation, the Lundberg Foundation, and HEROIC and CHILL (European Union integrated projects).

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Göndör, A., Ohlsson, R. Chromosome crosstalk in three dimensions. Nature 461, 212–217 (2009).

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