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Vol. 105, No. 2-4, 2004
Issue release date: 2004
Cytogenet Genome Res 105:292–301 (2004)

Spatial genome organization during T-cell differentiation

Kim S.H. · McQueen P.G. · Lichtman M.K. · Shevach E.M. · Parada L.A. · Misteli T.
aNational Cancer Institute, NIH; bMathematical and Statistical Laboratory, DCB, CIT, NIH, and cNational Institute of Allergy and Infectious Diseases, Laboratory of Immunology, Bethesda, MD (USA)

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The spatial organization of genomes within the mammalian cell nucleus is non-random. The functional relevance of spatial genome organization might be in influencing gene expression programs as cells undergo changes during development and differentiation. To gain insight into the plasticity of genomes in space and time and to correlate the activity of specific genes with their nuclear position, we systematically analyzed the spatial genome organization in differentiating mouse T-cells. We find significant global reorganization of centromeres, chromosomes and gene loci during the differentiation process. Centromeres were repositioned from a preferentially internal distribution in undifferentiated cells to a preferentially peripheral position in differentiated CD4+ and CD8+ cells. Chromosome 6, containing the differentially expressed T-cell markers CD4 and CD8, underwent differential changes in position depending on whether cells differentiated into CD4+ or CD8+ thymocytes. Similarly, the two marker loci CD4 and CD8 showed distinct behavior in their position relative to the chromosome 6 centromere at various stages of differentiation. Our results demonstrate that significant spatial genome reorganization occurs during differentiation and indicate that the relationship between dynamic genome topology and single gene regulation is highly complex.   

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  1. Abranches R, Beven AF, Aragon-Alcaide L, Shaw PJ: Transcription sites are not correlated with chromosome territories in wheat nuclei. J Cell Biol 143:5–12 (1998).
  2. Andrulis ED, Neiman AM, Zappulla DC, Sternglanz R: Perinuclear localization of chromatin facilitates transcriptional silencing. Nature 394:592–595 (1998).
  3. Bartova E, Kozubek S, Kozubek M, Jirsova P, Lukasova E, Skalnikova M, Cafourkova A, Koutna I: Nuclear topography of the c-myc gene in human leukemic cells. Gene 244:1–11 (2000).
  4. Boyle S, Gilchrist S, Bridger JM, Mahy NL, Ellis JA, Bickmore WA: The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. Hum Mol Genet 10:211–219 (2001).
  5. Bridger JM, Boyle S, Kill IR, Bickmore WA: Re-modelling of nuclear architecture in quiescent and senescent human fibroblasts. Curr Biol 10:149–152 (2000).
  6. Brown KE, Guest SS, Smale ST, Hahm K, Merkenschlager M, Fisher AG: Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell 91:845–854 (1997).
  7. Brown KE, Baxter J, Graf D, Merkenschlager M, Fisher AG: Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol Cell 3:207–217 (1999).
  8. Cai S, Han HJ, Kohwi-Shigematsu T: Tissue-specific nuclear architecture and gene expression regulated by SATB1. Nat Genet 34:42–51 (2003).
  9. Chaly N, Munro SB: Centromeres reposition to the nuclear periphery during L6E9 myogenesis in vitro. Exp Cell Res 223:274–278 (1996).
  10. Cheutin T, McNairn AJ, Jenuwein T, Gilbert DM, Singh PB, Misteli T: Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science 299:721–725 (2003).
  11. Choh V, De Boni U: Spatial repositioning of centromeric domains during regrowth of axons in nuclei of murine dorsal root ganglion neurons in vitro. J Neurobiol 31:325–332 (1996).
  12. Cook PR: Predicting three-dimensional genome structure from transcriptional activity. Nat Genet 32:347–352 (2002).
  13. Cremer T, Cremer C: Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nat Rev Genet 2:292–301 (2001).
  14. Croft JA, Bridger JM, Boyle S, Perry P, Teague P, Bickmore WA: Differences in the localization and morphology of chromosomes in the human nucleus. J Cell Biol 145:1119–1131 (1999).
  15. Dundr M, Misteli T: Functional architecture in the cell nucleus. Biochem J 356:297–310 (2001).
  16. Festenstein R, Pagakis SN, Hiragami K, Lyon D, Verreault A, Sekkali B, Kioussis D: Modulation of heterochromatin protein 1 dynamics in primary mammalian cells. Science 299:719–721 (2003).
  17. Fienberg SE (1982) in Kotz S, Johnson NL (eds): Encyclopedia of Statistical Science, pp 161–171 (Wiley and Sons, New York, 1982).
  18. Francastel C, Schubeler D, Martin DI, Groudine M: Nuclear compartmentalization and gene activity. Nat Rev mol Cell Biol 1:137–143 (2000).
  19. Francastel C, Magis W, Groudine M: Nuclear relocation of a transactivator subunit precedes target gene activation. Proc Natl Acad Sci USA 98: 12120–12125 (2001).
  20. Hochstrasser M, Mathog D, Gruenbaum Y, Saumweber H, Sedat JW: Spatial organization of chromosomes in the salivary gland nuclei of Drosophila melanogaster. J Cell Biol 102:112–123 (1986).
  21. Jin QW, Fuchs J, Loidl J: Centromere clustering is a major determinant of yeast interphase nuclear organization. J Cell Sci 113:1903–1912 (2000).
  22. Kioussis D, Ellmeier W: Chromatin and CD4, CD8A and CD8B gene expression during thymic differentiation. Nat Rev Immunol 2:909–919 (2002).
  23. Korenberg JR, Chen XN, Devon KL, Noya D, Oster-Granite ML, Birren BW: Mouse molecular cytogenetic resource: 157 BACs link the chromosomal and genetic maps. Genome Res 9:514–523 (1999).
  24. Kosak ST, Skok JA, Medina KL, Riblet R, Le Beau MM, Fisher AG, Singh H: Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 296:158–162 (2002).
  25. Kurz A, Lampel S, Nickolenko JE, Bradl J, Benner A, Zirbel RM, Cremer T, Lichter P: Active and inactive genes localize preferentially in the periphery of chromosome territories. J Cell Biol 135:1195–1205 (1996).
  26. Lamond AI, Earnshaw WC: Structure and function in the nucleus. Science 280:547–553 (1998).
  27. Lemon B, Tjian R: Orchestrated response: a symphony of transcription factors for gene control. Genes Dev 14:2551–2569 (2000).
  28. Lukasova E, Kozubek S, Kozubek M, Kjeronska J, Ryznar L, Horakova J, Krahulcova E, Horneck G: Localisation and distance between ABL and BCR genes in interphase nuclei of bone marrow cells of control donors and patients with chronic myeloid leukaemia. Hum Genet 100:525–535 (1997).
  29. Mahy NL, Perry PE, Bickmore WA: Gene density and transcription influence the localization of chromatin outside of chromosome territories detectable by FISH. J Cell Biol 159:753–763 (2002).
  30. Mahy NL, Perry PE, Gilchrist S, Baldock RA, Bickmore WA: Spatial organization of active and inactive genes and noncoding DNA within chromosome territories. J Cell Biol 157:579–589 (2002).
  31. Manuelidis L: Different central nervous system cell types display distinct and nonrandom arrangements of satellite DNA sequences. Proc Natl Acad Sci USA 81:3123–3127 (1984).
  32. Martou G, De Boni U: Nuclear topology of murine, cerebellar purkinje neurons: changes as a function of development. Exp Cell Res 256:131–139 (2000).
  33. Matera AG: Nuclear bodies: multifaceted subdomains of the interchromatin space. Trends Cell Biol 9:302–309 (1999).
  34. Misteli T, Spector DL: Serine/threonine phosphatase 1 modulates the subnuclear distribution of pre-mRNA splicing factors. Mol Biol Cell 7:1559–1572 (1996).
  35. Neves H, Ramos C, da Silva MG, Parreira A, Parreira L: The nuclear topography of ABL, BCR, PML, RARalpha genes: evidence for gene proximity in specific phases of the cell cycle and stages of hematopoietic differentiation. Blood 93:1197–1207 (1999).
  36. Nogami M, Kohda A, Taguchi H, Nakao M, Ikemura T, Okumura K: Relative locations of the centromere and imprinted SNRPN gene within chromosome 15 territories during the cell cycle in HL60 cells. J Cell Sci 113: 2157–2165 (2000).
  37. Parada L, Misteli T: Chromosome positioning in the interphase nucleus. Trends Cell Biol 12:425–432 (2002).
  38. Parada L, McQueen P, Munson P, Misteli T: Conservation of relative chromosome positioning in normal and cancer cells. Curr Biol 12: 1692–1697 (2002).
  39. Pederson T: Protein mobility within the nucleus – what are the right moves? Cell 104:635–638 (2001).
  40. Phair RD, Misteli T: High mobility of proteins in the mammalian cell nucleus. Nature 404:604–609 (2000).
  41. Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM: CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 196:237–246 (2002).
  42. Press WH, Teuolskky SA, Vettering WT, Flannery BP; in Press WH, Teuolskky SA, Vettering WT, Flannery BP (eds): Numerical Recipes in C, chapter 14 (Cambridge University Press, Cambridge UK, 1992).
  43. Roix JJ, McQueen PG, Munson PJ, Parada LA, Misteli T: Spatial proximity of translocation-prone gene loci in human lymphomas. Nat Genet 34:287–291 (2003).
  44. Sadoni N, Langer S, Fauth C, Bernardi G, Cremer T, Turner BM, Zink D: Nuclear organization of mammalian genomes. Polar chromosome territories build up functionally distinct higher order compartments. J Cell Biol 146:1211–1226 (1999).
  45. Skok JA, Brown KE, Azuara V, Caparros ML, Baxter J, Takacs K, Dillon N, Gray D, Perry RP, Merkenschlager M, Fisher AG: Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytes. Nat Immunol 2:848–854 (2001).
  46. Stevens MA (1982) in Kotz S, Johnson N (eds): Encyclopedia of Statistical Science, pp 393–396 (Wiley and Sons, New York, 1982).
  47. Sun HB, Shen J, Yokota H: Size-dependent positioning of human chromosomes in interphase nuclei. Biophys J 79:184–189 (2000).
  48. Tanabe H, Muller S, Neusser M, von Hase J, Calcagno E, Cremer M, Solovei I, Cremer C, Cremer T: Evolutionary conservation of chromosome territory arrangements in cell nuclei from higher primates. Proc Natl Acad Sci USA 99:4424–4429 (2002).
  49. Van Driel R, Fransz PF, Verschure PJ: The eukaryotic genome: a system regulated at different hierarchical levels. J Cell Sci 116:4067–4075 (2003).
  50. Volpi EV, Chevret E, Jones T, Vatcheva R, Williamson J, Beck S, Campbell RD, Goldsworthy M, Powis SH, Ragoussis J, Trowsdale J, Sheer D: Large-scale chromatin organization of the major histocompatibility complex and other regions of human chromosome 6 and its response to interferon in interphase nuclei. J Cell Sci 113:1565–1576 (2000).
  51. Wansink DG, Schul W, van der Kraan I, van Steensel B, van Driel R, de Jong L: Fluorescent labelling of nascent RNA reveals transcription by RNA polymerase II in domains scattered throughout the nucleus. J Cell Biol 122:282–293 (1993).
  52. Williams RR, Broad S, Sheer D, Ragoussis J: Subchromosomal positioning of the epidermal differentiation complex (EDC) in keratinocyte and lymphoblast interphase nuclei. Exp Cell Res 272:163–175 (2002).

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