Nuclear Architecture in Stem Cells

  • Kelly J. Morris
  • Mita Chotalia
  • Ana Pombo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 695)


Fundamental features of genome regulation depend on the linear DNA sequence, cell type specific modification of DNA and chromatin-associated proteins, which locally control the expression of single genes. Architectural features of genome organization within the three-dimensional (3D) nuclear space establish preferential positioning of genes relative to nuclear subcompartments associated with specific biochemical activities, thereby influencing states of expression. The structural and temporal organization of the genome within the nucleus of stem cells, together with specific features of epigenetic and transcriptional regulation are emerging as key players that influence pluripotency and differentiation.1,2


Embryonic Stem Cell Human Embryonic Stem Cell Nuclear Periphery Chromosome Territory Cajal Body 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Keenen B, de la Serna IL. Chromatin remodeling in embryonic stem cells: regulating the balance between pluripotency and differentiation. J Cell Physiol 2009; 219(1):1–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Meshorer E, Misteli T. Chromatin in pluripotent embryonic stem cells and differentiation. Nat Rev Mol Cell Biol 2006; 7(7):540–546.CrossRefPubMedGoogle Scholar
  3. 3.
    Branco MR, Pombo A. Intermingling of chromosome territories in interphase suggests role in translocations and transcription-dependent associations. PLoS Biol 2006; 4(5):e138.CrossRefGoogle Scholar
  4. 4.
    Lieberman-Aiden E, van Berkum NL, Williams L et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 2009; 326(5950):289–293.CrossRefPubMedGoogle Scholar
  5. 5.
    Parada L, Misteli T. Chromosome positioning in the interphase nucleus. Trends Cell Biol 2002; 12(9):425–432.CrossRefPubMedGoogle Scholar
  6. 6.
    Wiblin AE, Cui W, Clark AJ et al. Distinctive nuclear organisation of centromeres and regions involved in pluripotency in human embryonic stem cells. J Cell Sci 2005; 118(Pt 17):3861–3868.CrossRefPubMedGoogle Scholar
  7. 7.
    Bartova E, Galiova G, Krejci J et al. Epigenome and chromatin structure in human embryonic stem cells undergoing differentiation. Dev Dyn 2008; 237(12):3690–3702.CrossRefPubMedGoogle Scholar
  8. 8.
    Solovei I, Kreysing M, Lanctot C et al. Nuclear architecture of rod photoreceptor cells adapts to vision in mammalian evolution. Cell 2009; 137(2):356–368.CrossRefGoogle Scholar
  9. 9.
    Chambeyron S, Bickmore WA. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev 2004; 18(10):1119–1130.CrossRefPubMedGoogle Scholar
  10. 10.
    Morey C, Kress C, Bickmore WA. Lack of bystander activation shows that localization exterior to chromosome territories is not sufficient to up-regulate gene expression. Genome Res 2009; 19(7):1184–1194.CrossRefPubMedGoogle Scholar
  11. 11.
    Senner CE, Brockdorff N. Xist gene regulation at the onset of X inactivation. Curr Opin Genet Dev 2009; 19(2):122–126.CrossRefPubMedGoogle Scholar
  12. 12.
    Lee JT. Regulation of X-chromosome counting by Tsix and Xite sequences. Science 2005; 309(5735):768–771.CrossRefPubMedGoogle Scholar
  13. 13.
    Xu N, Tsai CL, Lee JT. Transient homologous chromosome pairing marks the onset of X inactivation. Science 2006; 311(5764):1149–1152.CrossRefPubMedGoogle Scholar
  14. 14.
    Bacher CP, Guggiari M, Brors B et al. Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nat Cell Biol 2006;8(3):293–299.CrossRefPubMedGoogle Scholar
  15. 15.
    Augui S, Filion GJ, Huart S et al. Sensing X chromosome pairs before X inactivation via a novel X-pairing region of the Xic. Science 2007; 318(5856):1632–1636.CrossRefPubMedGoogle Scholar
  16. 16.
    Xu N, Donohoe ME, Silva SS et al. Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein. Nat Genet 2007; 39(11):1390–1396.CrossRefPubMedGoogle Scholar
  17. 17.
    Khalil A, Grant JL, Caddle LB et al. Chromosome territories have a highly nonspherical morphology and nonrandom positioning. Chromosome Res 2007; 15(7):899–916.CrossRefPubMedGoogle Scholar
  18. 18.
    Scialdone A, Nicodemi M. Mechanics and dynamics of X-chromosome pairing at X inactivation. PLoS Comput Biol 2008; 4(12):e1000244.CrossRefPubMedGoogle Scholar
  19. 19.
    Tsai CL, Rowntree RK, Cohen DE et al. Higher order chromatin structure at the X-inactivation center via looping DNA. Dev Biol 2008; 319(2):416–425.CrossRefPubMedGoogle Scholar
  20. 20.
    Eils R, Dietzel S, Bertin E et al. Three-dimensional reconstruction of painted human interphase chromosomes: active and inactive X chromosome territories have similar volumes but differ in shape and surface structure. J Cell Biol 1996; 135(6 Pt 1):1427–1440.CrossRefPubMedGoogle Scholar
  21. 21.
    Chaumeil J, Le Baccon P, Wutz A et al. A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev 2006; 20(16):2223–2237.CrossRefPubMedGoogle Scholar
  22. 22.
    Butler JT, Hall LL, Smith KP et al. Changing nuclear landscape and unique PML structures during early epigenetic transitions of human embryonic stem cells. J Cell Biochem 2009; 107(4):609–621.CrossRefPubMedGoogle Scholar
  23. 23.
    Gruenbaum Y, Margalit A, Goldman RD et al. The nuclear lamina comes of age. Nat Rev Mol Cell Biol 2005; 6(1):21–31.CrossRefPubMedGoogle Scholar
  24. 24.
    Francastel C, Schubeler D, Martin DI et al. Nuclear compartmentalization and gene activity. Nat Rev Mol Cell Biol 2000; 1(2):137–143.CrossRefPubMedGoogle Scholar
  25. 25.
    Akhtar A, Gasser SM. The nuclear envelope and transcriptional control. Nat Rev Genet 2007; 8(7):507–517.CrossRefPubMedGoogle Scholar
  26. 26.
    Finlan LE, Sproul D, Thomson I et al. Recruitment to the nuclear periphery can alter expression of genes in human cells. PLoS Genet 2008; 4(3):e1000039.CrossRefPubMedGoogle Scholar
  27. 27.
    Ragoczy T, Bender MA, Telling A et al. The locus control region is required for association of the murine beta-globin locus with engaged transcription factories during erythroid maturation. Genes Dev 2006; 20(11):1447–1457.CrossRefPubMedGoogle Scholar
  28. 28.
    Williams RR, Azuara V, Perry P et al. Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus. J Cell Sci 2006; 119(Pt 1):132–140.CrossRefPubMedGoogle Scholar
  29. 29.
    Kosak ST, Skok JA, Medina KL et al. Subnuclear compartmentalization of immunoglobulin loci during lymphocyte development. Science 2002; 296(5565):158–162.CrossRefPubMedGoogle Scholar
  30. 30.
    Hewitt SL, High FA, Reiner SL et al. Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiation. Eur J Immunol 2004; 34(12):3604–3613.CrossRefPubMedGoogle Scholar
  31. 31.
    Constantinescu D, Gray HL, Sammak PJ et al. Lamin A/C expression is a marker of mouse and human embryonic stem cell differentiation. Stem Cells 2006; 24(1):177–185.CrossRefPubMedGoogle Scholar
  32. 32.
    Pajerowski JD, Dahl KN, Zhong FL et al. Physical plasticity of the nucleus in stem cell differentiation. Proc Natl Acad Sci USA 2007; 104(40):15619–15624.CrossRefPubMedGoogle Scholar
  33. 33.
    Luo L, Gassman KL, Petell LM et al. The nuclear periphery of embryonic stem cells is a transcriptionally permissive and repressive compartment. J Cell Sci 2009; 122(Pt 20):3729–3737.CrossRefPubMedGoogle Scholar
  34. 34.
    Kaiser TE, Intine RV, Dundr M. De novo formation of a subnuclear body. Science 2008; 322(5908):1713–1717.CrossRefPubMedGoogle Scholar
  35. 35.
    Misteli T. Self-organization in the genome. Proc Natl Acad Sci USA 2009; 106(17):6885–6886.CrossRefPubMedGoogle Scholar
  36. 36.
    Hall LL, Smith KP, Byron M et al. Molecular anatomy of a speckle. Anat Rec A Discov Mol Cell Evol Biol 2006; 288(7):664–675.PubMedGoogle Scholar
  37. 37.
    Xie SQ, Martin S, Guillot PV et al. Splicing speckles are not reservoirs of RNA polymerase II, but contain an inactive form, phosphorylated on serine2 residues of the C-terminal domain. Mol Biol Cell 2006; 17(4):1723–1733.CrossRefPubMedGoogle Scholar
  38. 38.
    Lawrence JB, Clemson CM. Gene associations: true romance or chance meeting in a nuclear neighborhood? J Cell Biol 2008; 182(6):1035–1038.CrossRefPubMedGoogle Scholar
  39. 39.
    Morris GE. The Cajal body. Biochim Biophys Acta 2008; 1783(11):2108–2115.PubMedGoogle Scholar
  40. 40.
    Schwartz YB, Pirrotta V. Polycomb complexes and epigenetic states. Curr Opin Cell Biol 2008; 20(3):266–273.CrossRefPubMedGoogle Scholar
  41. 41.
    Brookes E, Pombo A. Modifications of RNA polymerase II are pivotal in regulating gene expression states. EMBO Rep 2009; 10(11):1213–1219.CrossRefPubMedGoogle Scholar
  42. 42.
    Bernstein E, Duncan EM, Masui O et al. Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol 2006; 26(7):2560–2569.CrossRefPubMedGoogle Scholar
  43. 43.
    Ren X, Vincenz C, Kerppola TK. Changes in the distributions and dynamics of polycomb repressive complexes during embryonic stem cell differentiation. Mol Cell Biol 2008; 28(9):2884–2895.CrossRefPubMedGoogle Scholar
  44. 44.
    Bancaud A, Huet S, Daigle N et al. Molecular crowding affects diffusion and binding of nuclear proteins in heterochromatin and reveals the fractal organization of chromatin. EMBO J 2009; 28(24):3785–3798.CrossRefPubMedGoogle Scholar
  45. 45.
    Kimura H, Cook PR. Kinetics of core histones in living human cells: little exchange of H3 and H4 and some rapid exchange of H2B. J Cell Biol 2001; 153(7):1341–1353.CrossRefPubMedGoogle Scholar
  46. 46.
    Phair RD, Scaffidi P, Elbi C et al. Global nature of dynamic protein-chromatin interactions in vivo: three-dimensional genome scanning and dynamic interaction networks of chromatin proteins. Mol Cell Biol 2004; 24(14):6393–6402.CrossRefPubMedGoogle Scholar
  47. 47.
    Giglia-Mari G, Theil AF, Mari PO et al. Differentiation driven changes in the dynamic organization of Basal transcription initiation. PLoS Biol 2009; 7(10):e1000220.CrossRefPubMedGoogle Scholar
  48. 48.
    Cheutin T, McNairn AJ, Jenuwein T et al. Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science 2003; 299(5607):721–725.CrossRefPubMedGoogle Scholar
  49. 49.
    Festenstein R, Pagakis SN, Hiragami K et al. Modulation of heterochromatin protein 1 dynamics in primary Mammalian cells. Science 2003; 299(5607):719–721.CrossRefPubMedGoogle Scholar
  50. 50.
    Misteli T, Gunjan A, Hock R et al. Dynamic binding of histone H1 to chromatin in living cells. Nature 2000; 408(6814):877–881.CrossRefPubMedGoogle Scholar
  51. 51.
    Meshorer E, Yellajoshula D, George E et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev Cell 2006; 10(1):105–116.CrossRefPubMedGoogle Scholar
  52. 52.
    Aoto T, Saitoh N, Ichimura T et al. Nuclear and chromatin reorganization in the MHC-Oct3/4 locus at developmental phases of embryonic stem cell differentiation. Dev Biol 2006; 298(2):354–367.CrossRefPubMedGoogle Scholar
  53. 53.
    Kobayakawa S, Miike K, Nakao M et al. Dynamic changes in the epigenomic state and nuclear organization of differentiating mouse embryonic stem cells. Genes Cells 2007; 12(4):447–460.CrossRefPubMedGoogle Scholar
  54. 54.
    Cammas F, Oulad-Abdelghani M, Vonesch JL et al. Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction. J Cell Sci 2002; 115(Pt 17):3439–3448.PubMedGoogle Scholar
  55. 55.
    Efroni S, Duttagupta R, Cheng J et al. Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2008; 2(5):437–447.CrossRefPubMedGoogle Scholar
  56. 56.
    Bibikova M, Chudin E, Wu B et al. Human embryonic stem cells have a unique epigenetic signature. Genome Res 2006; 16(9):1075–1083.CrossRefPubMedGoogle Scholar
  57. 57.
    Gaspar-Maia A, Alajem A, Polesso F et al. Chd1 regulates open chromatin and pluripotency of embryonic stem cells. Nature 2009; 460(7257):863–868.PubMedGoogle Scholar
  58. 58.
    Faro-Trindade I, Cook PR. A conserved organization of transcription during embryonic stem cell differentiation and in cells with high C value. Mol Biol Cell 2006; 17(7):2910–2920.CrossRefPubMedGoogle Scholar
  59. 59.
    Donaldson AD. Shaping time: chromatin structure and the DNA replication programme. Trends Genet 2005; 21(8):444–449.CrossRefPubMedGoogle Scholar
  60. 60.
    Perry P, Sauer S, Billon N et al. A dynamic switch in the replication timing of key regulator genes in embryonic stem cells upon neural induction. Cell Cycle 2004; 3(12):1645–1650.PubMedGoogle Scholar
  61. 61.
    Hiratani I, Ryba T, Itoh M et al. Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol 2008; 6(10):e245.CrossRefPubMedGoogle Scholar
  62. 62.
    Hiratani I, Leskovar A, Gilbert DM. Differentiation-induced replication-timing changes are restricted to AT-rich/long interspersed nuclear element (LINE)-rich isochores. Proc Natl Acad Sci USA 2004; 101(48):16861–16866.CrossRefPubMedGoogle Scholar
  63. 63.
    Goren A, Cedar H. Replicating by the clock. Nat Rev Mol Cell Biol 2003; 4(1):25–32.CrossRefPubMedGoogle Scholar
  64. 64.
    Azuara V, Perry P, Sauer S et al. Chromatin signatures of pluripotent cell lines. Nat Cell Biol 2006; 8(5):532–538.CrossRefPubMedGoogle Scholar
  65. 65.
    Bernstein BE, Mikkelsen TS, Xie X et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 2006; 125(2):315–326.CrossRefPubMedGoogle Scholar
  66. 66.
    Stock JK, Giadrossi S, Casanova M et al. Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nat Cell Biol 2007; 9(12):1428–1435.CrossRefPubMedGoogle Scholar
  67. 67.
    Mikkelsen TS, Ku M, Jaffe DB et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 2007; 448(7153):553–560.CrossRefPubMedGoogle Scholar
  68. 68.
    Cui K, Zang C, Roh TY et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 2009; 4(1):80–93.CrossRefPubMedGoogle Scholar
  69. 69.
    Mohn F, Weber M, Rebhan M et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell 2008; 30(6):755–766.CrossRefPubMedGoogle Scholar
  70. 70.
    Rodriguez J, Munoz M, Vives L et al. Bivalent domains enforce transcriptional memory of DNA methylated genes in cancer cells. Proc Natl Acad Sci USA 2008; 105(50):19809–19814.CrossRefPubMedGoogle Scholar
  71. 71.
    McGarvey KM, Van Neste L, Cope L et al. Defining a chromatin pattern that characterizes DNA-hypermethylated genes in colon cancer cells. Cancer Res 2008; 68(14):5753–5759.CrossRefPubMedGoogle Scholar
  72. 72.
    Lim PS, Hardy K, Bunting KL et al. Defining the chromatin signature of inducible genes in T-cells. Genome Biol 2009; 10(10):R107.CrossRefPubMedGoogle Scholar
  73. 73.
    Araki Y, Wang Z, Zang C et al. Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T-cells. Immunity 2009; 30(6):912–925.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Genome Function Group, MRC Clinical Sciences Centre, Imperial College School of MedicineHammersmith Hospital CampusLondonUK

Personalised recommendations