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Genomics tools for unraveling chromosome architecture

Abstract

The spatial organization of chromosomes inside the cell nucleus is still poorly understood. This organization is guided by intra- and interchromosomal contacts and by interactions of specific chromosomal loci with relatively fixed nuclear 'landmarks' such as the nuclear envelope and the nucleolus. Researchers have begun to use new molecular genome-wide mapping techniques to uncover both types of molecular interactions, providing insights into the fundamental principles of interphase chromosome folding.

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Figure 1: Cartoon of nucleus depicting the spatial interactions that contribute to the overall architecture of interphase chromosomes.
Figure 2: Mapping of interactions of the genome with nuclear landmarks, here shown for the nuclear lamina.
Figure 3: Principles of the major 3C-based technologies.
Figure 4: Speculative cartoon model of chromatin organization.

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References

  1. Pombo, A. & Branco, M.R. Functional organisation of the genome during interphase. Curr. Opin. Genet. Dev. 17, 451–455 (2007).

    Article  CAS  Google Scholar 

  2. Misteli, T. Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 (2007).

    Article  CAS  Google Scholar 

  3. Zhao, R., Bodnar, M.S. & Spector, D.L. Nuclear neighborhoods and gene expression. Curr. Opin. Genet. Dev. 19, 172–179 (2009).

    Article  CAS  Google Scholar 

  4. Hetzer, M.W. & Wente, S.R. Border control at the nucleus: biogenesis and organization of the nuclear membrane and pore complexes. Dev. Cell 17, 606–616 (2009).

    Article  CAS  Google Scholar 

  5. Stuurman, N., Heins, S. & Aebi, U. Nuclear lamins: their structure, assembly, and interactions. J. Struct. Biol. 122, 42–66 (1998).

    Article  CAS  Google Scholar 

  6. Herrmann, H. & Aebi, U. Intermediate filaments: molecular structure, assembly mechanism, and integration into functionally distinct intracellular Scaffolds. Annu. Rev. Biochem. 73, 749–789 (2004).

    Article  CAS  Google Scholar 

  7. Prokocimer, M. et al. Nuclear lamins: key regulators of nuclear structure and activities. J. Cell Mol. Med. 13, 1059–1085 (2009).

    Article  CAS  Google Scholar 

  8. Franke, W.W. Structure, biochemistry, and functions of the nuclear envelope. Int. Rev. Cytol. 4 (suppl.), 71–236 (1974).

    CAS  PubMed  Google Scholar 

  9. Blobel, G. Gene gating: a hypothesis. Proc. Natl. Acad. Sci. USA 82, 8527–8529 (1985).

    Article  CAS  Google Scholar 

  10. Takizawa, T., Meaburn, K.J. & Misteli, T. The meaning of gene positioning. Cell 135, 9–13 (2008).

    Article  CAS  Google Scholar 

  11. Fedorova, E. & Zink, D. Nuclear genome organization: common themes and individual patterns. Curr. Opin. Genet. Dev. 19, 166–171 (2009).

    Article  CAS  Google Scholar 

  12. Greil, F., Moorman, C. & van Steensel, B. DamID: mapping of in vivo protein-genome interactions using tethered DNA adenine methyltransferase. Methods Enzymol. 410, 342–359 (2006).

    Article  CAS  Google Scholar 

  13. Vogel, M.J., Peric-Hupkes, D. & van Steensel, B. Detection of in vivo protein-DNA interactions using DamID in mammalian cells. Nat. Protoc. 2, 1467–1478 (2007).

    Article  CAS  Google Scholar 

  14. Pickersgill, H. et al. Characterization of the Drosophila melanogaster genome at the nuclear lamina. Nat. Genet. 38, 1005–1014 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Peric-Hupkes, D. et al. Molecular maps of the reorganization of genome— nuclear lamina interactions during differentiation. Mol. Cell 38, 603–613 (2010).

    Article  CAS  Google Scholar 

  17. Shevelyov, Y.Y. et al. The B-type lamin is required for somatic repression of testis-specific gene clusters. Proc. Natl. Acad. Sci. USA 106, 3282–3287 (2009).

    Article  CAS  Google Scholar 

  18. Reddy, K.L., Zullo, J.M., Bertolino, E. & Singh, H. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452, 243–247 (2008).

    Article  CAS  Google Scholar 

  19. Finlan, L.E. et al. Recruitment to the nuclear periphery can alter expression of genes in human cells. PLoS Genet. 4, e1000039 (2008).

    Article  Google Scholar 

  20. Kumaran, R.I. & Spector, D.L. A genetic locus targeted to the nuclear periphery in living cells maintains its transcriptional competence. J. Cell Biol. 180, 51–65 (2008).

    Article  CAS  Google Scholar 

  21. Casolari, J.M. et al. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117, 427–439 (2004).

    Article  CAS  Google Scholar 

  22. Brown, C.R., Kennedy, C.J., Delmar, V.A., Forbes, D.J. & Silver, P.A. Global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexes. Genes Dev. 22, 627–639 (2008).

    Article  CAS  Google Scholar 

  23. Kalverda, B., Pickersgill, H., Shloma, V.V. & Fornerod, M. Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm. Cell 140, 360–371 (2010).

    Article  CAS  Google Scholar 

  24. Capelson, M. et al. Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes. Cell 140, 372–383 (2010).

    Article  CAS  Google Scholar 

  25. Vaquerizas, J.M. et al. Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome. PLoS Genet. 6, e1000846 (2010).

    Article  Google Scholar 

  26. Schermelleh, L. et al. Subdiffraction multicolor imaging of the nuclear periphery with 3D structured illumination microscopy. Science 320, 1332–1336 (2008).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  28. Stahl, A., Hartung, M., Vagner-Capodano, A.M. & Fouet, C. Chromosomal constitution of nucleolus-associated chromatin in man. Hum. Genet. 35, 27–34 (1976).

    Article  CAS  Google Scholar 

  29. Thompson, M., Haeusler, R.A., Good, P.D. & Engelke, D.R. Nucleolar clustering of dispersed tRNA genes. Science 302, 1399–1401 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. 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).

    Article  CAS  Google Scholar 

  32. Murrell, A., Heeson, S. & Reik, W. Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops. Nat. Genet. 36, 889–893 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. 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).

    Article  CAS  Google Scholar 

  38. 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. Nat. Genet. 37, 31–40 (2005).

    Article  CAS  Google Scholar 

  39. Tiwari, V.K., Cope, L., McGarvey, K.M., Ohm, J.E. & Baylin, S.B. A novel 6C assay uncovers Polycomb-mediated higher order chromatin conformations. Genome Res. 18, 1171–1179 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Simonis, M., Kooren, J. & de Laat, W. An evaluation of 3C-based methods to capture DNA interactions. Nat. Methods 4, 895–901 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Xu, N., Tsai, C.L. & Lee, J.T. Transient homologous chromosome pairing marks the onset of X inactivation. Science 311, 1149–1152 (2006).

    Article  CAS  Google Scholar 

  44. Bacher, C.P. et al. Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nat. Cell Biol. 8, 293–299 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  46. Sandhu, K.S. et al. Nonallelic transvection of multiple imprinted loci is organized by the H19 imprinting control region during germline development. Genes Dev. 23, 2598–2603 (2009).

    Article  CAS  Google Scholar 

  47. Rodley, C.D., Bertels, F., Jones, B. & O'Sullivan, J.M. Global identification of yeast chromosome interactions using genome conformation capture. Fungal Genet. Biol. 46, 879–886 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  50. 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).

    Article  CAS  Google Scholar 

  51. Dekker, J. Mapping in vivo chromatin interactions in yeast suggests an extended chromatin fiber with regional variation in compaction. J. Biol. Chem. 283, 34532–34540 (2008).

    Article  CAS  Google Scholar 

  52. Taddei, A., Schober, H. & Gasser, S.M. The budding yeast nucleus. Cold Spring Harb. Perspect. Biol. 2, a000612 (2010).

    Article  Google Scholar 

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

    Article  Google Scholar 

  54. Schwaiger, M. et al. Chromatin state marks cell-type- and gender-specific replication of the Drosophila genome. Genes Dev. 23, 589–601 (2009).

    Article  CAS  Google Scholar 

  55. O'Keefe, R.T., Henderson, S.C. & Spector, D.L. Dynamic organization of DNA replication in mammalian cell nuclei: spatially and temporally defined replication of chromosome-specific α-satellite DNA sequences. J. Cell Biol. 116, 1095–1110 (1992).

    Article  CAS  Google Scholar 

  56. Ryba, T. et al. Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types. Genome Res. 20, 761–770 (2010).

    Article  CAS  Google Scholar 

  57. Wen, B., Wu, H., Shinkai, Y., Irizarry, R.A. & Feinberg, A.P. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat. Genet. 41, 246–250 (2009).

    Article  CAS  Google Scholar 

  58. Yokochi, T. et al. G9a selectively represses a class of late-replicating genes at the nuclear periphery. Proc. Natl. Acad. Sci. USA 106, 19363–19368 (2009).

    Article  CAS  Google Scholar 

  59. Gilbert, N. et al. Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell 118, 555–566 (2004).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  61. 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).

    Article  CAS  Google Scholar 

  62. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  64. Chuang, C.H. & Belmont, A.S. Moving chromatin within the interphase nucleus-controlled transitions? Semin. Cell Dev. Biol. 18, 698–706 (2007).

    Article  CAS  Google Scholar 

  65. Bolzer, A. et al. Three-dimensional maps of all chromosomes in human male fibroblast nuclei and prometaphase rosettes. PLoS Biol. 3, e157 (2005).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  67. 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).

    Article  CAS  Google Scholar 

  68. 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).

    Article  Google Scholar 

  69. Shaw, C.J. & Lupski, J.R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13 Spec No 1, R57–R64 (2004).

    Article  CAS  Google Scholar 

  70. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233–245 (2007).

    Article  CAS  Google Scholar 

  71. Harewood, L. et al. The effect of translocation-induced nuclear reorganization on gene expression. Genome Res. 20, 554–564 (2010).

    Article  CAS  Google Scholar 

  72. Simonis, M. et al. High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology. Nat. Methods 6, 837–842 (2009).

    Article  CAS  Google Scholar 

  73. Roix, J.J., McQueen, P.G., Munson, P.J., Parada, L.A. & Misteli, T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nat. Genet. 34, 287–291 (2003).

    Article  CAS  Google Scholar 

  74. Lin, C. et al. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139, 1069–1083 (2009).

    Article  CAS  Google Scholar 

  75. Mani, R.S. et al. Induced chromosomal proximity and gene fusions in prostate cancer. Science 326, 1230 (2009).

    Article  CAS  Google Scholar 

  76. Worman, H.J., Fong, L.G., Muchir, A. & Young, S.G. Laminopathies and the long strange trip from basic cell biology to therapy. J. Clin. Invest. 119, 1825–1836 (2009).

    Article  CAS  Google Scholar 

  77. Goldman, R.D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. USA 101, 8963–8968 (2004).

    Article  CAS  Google Scholar 

  78. Taimen, P. et al. A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization. Proc. Natl. Acad. Sci. USA 106, 20788–20793 (2009).

    Article  CAS  Google Scholar 

  79. Pegoraro, G. et al. Ageing-related chromatin defects through loss of the NURD complex. Nat. Cell Biol. 11, 1261–1267 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank members of the van Steensel and Dekker labs and M. Walhout for suggestions. This work was supported by the Netherlands Genomics Initiative and an Netherlands Organization for Scientific Research–Earth and Life Sciences (NWO-ALW) VICI grant to B.v.S., a grant from the US National Institutes of Health (HG003143) and a W.M. Keck Foundation Distinguished Young Scholar Award to J.D.

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van Steensel, B., Dekker, J. Genomics tools for unraveling chromosome architecture. Nat Biotechnol 28, 1089–1095 (2010). https://doi.org/10.1038/nbt.1680

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