Advertisement

Ikaros-Family Proteins: In Search of Molecular Functions During Lymphocyte Development

  • B. S. Cobb
  • S. T. Smale
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 290)

Abstract

The regulatory steps that lead to the differentiation of hematopoietic cells from a multipotential stem cell remain largely unknown. A beginning to the understanding of these steps has come from the study of DNA-binding proteins that are thought to regulate the expression of genes required for specific developmental events. Ikaros is the founding member of a small family of DNA-binding proteins required for lymphocyte development, but the members of this family differ from other key regulators of lymphopoiesis in that direct target genes have not been conclusively identified, and reasonable support has been presented for only a few potential targets. Therefore, the molecular mechanisms that Ikaros uses for regulating lymphocyte development remain largely unknown. Current data suggest that, in some instances, Ikaros may function as a typical transcription factor. However, recent results suggest that it may function more broadly, perhaps in the formation of silent and active chromatin structures. In this review, our current knowledge of the molecular functions of Ikaros will be discussed.

Keywords

Centromeric Heterochromatin Pericentromeric Heterochromatin Lymphocyte Development Typical Transcription Factor Histone Deacetylase Complex 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Avitahl N, Winandy S, Friedrich C, Jones B, Yimin G, Georgopoulos K (1999) Ikaros sets thresholds for T cell activation and regulates chromosome propagation. Immunity 10:333–343PubMedCrossRefGoogle Scholar
  2. Bernat RL, Borisy GG, Rothfield NF, Earnshaw WC (1990) Injection of anticentromere antibodies in interphase disrupts events required for chromosome movement at mitosis. J Cell Biol 111:1519–1533PubMedCrossRefGoogle Scholar
  3. Bernat RL, Delannoy MR, Rothfield NF, Earnshaw WC (1991) Disruption of centromere assembly during interphase inhibits kinetochore morphogenesis and function in mitosis. Cell 66:1229–1238PubMedCrossRefGoogle Scholar
  4. Brown KE, Guest SS, Smale ST, Hahm K, Merkenschlager M, Fisher AG (1997) Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell 91:845–854PubMedCrossRefGoogle Scholar
  5. Brown KE, Baxter J, Graf D, Merkenschlager M, Fisher AG (1999) Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. Mol Cell 3:207–217PubMedCrossRefGoogle Scholar
  6. Choo KH, Vissel B, Nagy A, Earle E, Kalitsis P (1991) A survey of the genomic distribution of alpha satellite DNA on all the human chromosomes, and derivation of a new consensus sequence. Nucleic Acids Res 19:1179–1182PubMedGoogle Scholar
  7. Clevers HC, Grosschedl R (1996) Transcriptional control of lymphoid development: lessons from gene targeting. Immunol Today 17:336–343PubMedCrossRefGoogle Scholar
  8. Clevers HC, Oosterwegel MA, Georgopoulos K (1993) Transcription factors in early T-cell development. Immunol Today 14:591–596PubMedCrossRefGoogle Scholar
  9. Cobb BS, Morales-Alcelay S, Kleiger G, Brown KE, Fisher AG, Smale ST (2000) Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. Genes Dev 14:2146–2160PubMedCrossRefGoogle Scholar
  10. Cortes M, Wong E, Koipally J, Georgopoulos K (1999) Control of lymphocyte development by the Ikaros gene family. Curr Op Immunol 11:167–171CrossRefGoogle Scholar
  11. Csink AK, Henikoff S (1998) Something from nothing: the evolution and utility of satellite repeats. Trends Genet 14:200–204PubMedCrossRefGoogle Scholar
  12. Dumortier A, Kirstetter P, Kastner P, Chan S (2003) Ikaros regulates neutrophil differentiation. Blood 101:2219–2226PubMedCrossRefGoogle Scholar
  13. Ernst P, Hahm K, Smale ST (1993) Both LyF-1 and an Ets protein interact with a critical promoter element in the murine terminal transferase gene. Mol Cell Biol 13:2982–2992PubMedGoogle Scholar
  14. Ernst P, Hahm K, Trinh L, Davis JN, Roussel MF, Turck CW, Smale ST (1996) A potential role for Elf-1 in terminal transferase gene regulation. Mol Cell Biol 16:6121–6131PubMedGoogle Scholar
  15. Ferreira J, Paolella G, Ramos C, Lamond AI (1997) Spatial organization of large-scale chromatin domains in the nucleus: a magnified view of single chromosome territories. J Cell Biol 139:1597–1610PubMedCrossRefGoogle Scholar
  16. Georgopoulos K (1997) Transcription factors required for lymphoid lineage commitment. Curr Opin Immunol 9:222–227PubMedCrossRefGoogle Scholar
  17. Georgopoulos K (2002) Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nature Rev Immunol 2:162–174CrossRefGoogle Scholar
  18. Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, Sharpe A (1994) The Ikaros gene is required for the development of all lymphoid lineages. Cell 79:143–156PubMedCrossRefGoogle Scholar
  19. Georgopoulos K, Moore DD, Derfler B (1992) Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science 258:808–812PubMedGoogle Scholar
  20. Georgopoulos K, Winandy S, Avitahl N (1997) The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol 15:155–176PubMedCrossRefGoogle Scholar
  21. Glimcher LH, Singh H (1999) Transcription factors in lymphocyte development—T B cells get together. Cell 96:13–23PubMedCrossRefGoogle Scholar
  22. Hahm K, Cobb BS, McCarty AS, Brown KE, Klug CA, Lee R, Akashi K, Weissman IL, Fisher AG, Smale ST (1998) Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes Dev 12:782–796PubMedGoogle Scholar
  23. Hahm K, Ernst P, Lo K, Kim GS, Turck C, Smale ST (1994) The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene. Mol Cell Biol 14:7111–7123PubMedGoogle Scholar
  24. Hansen JD, Strassburger P, Du Pasquier L (1997) Conservation of a master hematopoietic switch gene during vertebrate evolution: isolation and characterization of Ikaros from teleost and amphibian species. Eur J Immunol 27:3049–3058PubMedGoogle Scholar
  25. Harker N, Naito T, Cortes M, Hostert A, Hirschberg S, Tolaini M, Roderick K, Georgopoulos K, Kioussis D (2002) The CD8alpha gene locus is regulated by the Ikaros family of proteins. Mol Cell 10:1403–1415PubMedCrossRefGoogle Scholar
  26. Honma Y, Kiyosawa H, Mori T, Oguri A, Nikaido T, Kanazawa K, Tojo M, Takeda J, Tanno, Y, Yokoya S et al. (1999) Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system. FEBS Letters 447:76–80PubMedCrossRefGoogle Scholar
  27. Karpen GH, Allshire RC (1997) The case for epigenetic effects on centromere identity and function. Trends Genet 13:489–496PubMedCrossRefGoogle Scholar
  28. Kelley CM, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K, Morgan BA (1998) Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Curr Biol 8:508–515PubMedCrossRefGoogle Scholar
  29. Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T et al. (1999) Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10:345–355PubMedCrossRefGoogle Scholar
  30. Kipling D, Warburton PE (1997) Centromeres, CENP-B Tigger too. Trends Genet 13:141–145PubMedCrossRefGoogle Scholar
  31. Kirstetter P, Thomas M, Dierich A, Kastner P, Chan S (2002) Ikaros is critical for B cell differentiation and function. Eur J Immunol 32:720–730PubMedCrossRefGoogle Scholar
  32. Klug CA, Morrison SJ, Masek M, Hahm K, Smale ST, Weissman IL (1998) Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, Ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci USA 95:657–662PubMedCrossRefGoogle Scholar
  33. Koipally J, Renold A, Kim J, Georgopoulos K (1999) Repression by Ikaros Aiolos is mediated through histone deacetylase complexes. EMBO J 18:3090–3100PubMedCrossRefGoogle Scholar
  34. Koipally J, Georgopoulos K (2000) Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity. J Biol Chem 275:19594–19602PubMedCrossRefGoogle Scholar
  35. Kurz A, Lampel S, Nickolenko JE, Bradl J, Benner A, Zirbel RM, Cremer T, Lichter P (1996) Active and inactive genes localize preferentially in the periphery of chromosome territories. J Cell Biol 135:1195–1205PubMedCrossRefGoogle Scholar
  36. Lamond AI, Earnshaw WC (1998) Structure and function in the nucleus. Science 280:547–553PubMedCrossRefGoogle Scholar
  37. Liippo J, Lassila O (1997) Avian Ikaros gene is expressed early in embryogenesis. Eur J Immunol 27:1853–1857PubMedGoogle Scholar
  38. Lo K, Landau NR, Smale ST (1991) LyF-1, a transcriptional regulator that interacts with a novel class of promoters for lymphocyte-specific genes. Mol Cell Biol 11:5229–5243PubMedGoogle Scholar
  39. Masumoto H, Sugimoto K, Okazaki T (1989) Alphoid satellite DNA is tightly associated with centromere antigens in human chromosomes throughout the cell cycle. Exp Cell Res 181:181–196PubMedCrossRefGoogle Scholar
  40. McCarty AS, Kleiger G, Eisenberg D, Smale ST (2003) Selective dimerization of a C2H2 zinc finger subfamily. Mol Cell 11:459–470PubMedCrossRefGoogle Scholar
  41. MolnQr A, Georgopoulos K (1994) The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol 14:8292–8303Google Scholar
  42. MolnQr A, Wu P, Largespada DA, Vortkamp A, Scherer S, Copeland NG, Jenkins NA, Bruns G, Georgopoulos K (1996) The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. J Immunol 156:585–592Google Scholar
  43. Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, Wu P, Neben S, Georgopoulos K (1997) Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J 16:2004–2013PubMedCrossRefGoogle Scholar
  44. Murphy TD, Karpen GH (1998) Centromeres take flight: alpha satellite and the quest for the human centromere. Cell 93:317–320PubMedCrossRefGoogle Scholar
  45. Nichogiannopoulou A, Trevisan M, Friedrich C, Georgopoulos K (1998) Ikaros in hemopoietic lineage determination and homeostasis. Semin Immunol 10:119–125PubMedCrossRefGoogle Scholar
  46. Nichogiannopoulou A, Trevisan M, Neben S, Friedrich C, Georgopoulos K (1999) Defects in hemopoietic stem cell activity in Ikaros mutant mice. J Exp Med 190:1201–1214PubMedCrossRefGoogle Scholar
  47. O'Neill LP, Turner BM (1995) Histone H4 acetylation distinguishes coding regions of the human genome from heterochromatin in a differentiation-dependent but transcription-independent manner. EMBO J 14:3946–3957PubMedGoogle Scholar
  48. Orkin SH (1995) Hematopoiesis: how does it happen? Curr Opin Cell Biol 7:870–877PubMedCrossRefGoogle Scholar
  49. Papathanasiou P, Perkins AC, Cobb BS, Ferrini R, Sridharan R, Hoyne GF, Nelms KA, Smale ST, Goodnow CC (2003) Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor. Immunity 19:131–144PubMedCrossRefGoogle Scholar
  50. Perdomo J, Holmes M, Chong B, Crossley M (2000) Eos and Pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities. J Biol Chem 275:38347–38354PubMedCrossRefGoogle Scholar
  51. Platero JS, Csink AK, Quintanilla A, Henikoff S (1998) Changes in chromosomal localization of heterochromatin-binding proteins during the cell cycle in Drosophila. J Cell Biol 140:1297–1306PubMedCrossRefGoogle Scholar
  52. Pluta AF, Mackay AM, Ainsztein AM, Goldberg IG, Earnshaw WC (1995) The centromere: hub of chromosomal activities. Science 270:1591–1594PubMedGoogle Scholar
  53. Poux S, Kostic C, Pirrotta V (1996) Hunchback-independent silencing of late Ubx enhancers by a Polycomb Group Response Element. EMBO J 15:4713–4722PubMedGoogle Scholar
  54. Sabbattini P, Lundgren M, Georgiou A, Chow C, Warnes G, Dillon N (2001) Binding of Ikaros to the lambda5 promoter silences transcription through a mechanism that does not require heterochromatin formation. EMBO J 20:2812–2822PubMedCrossRefGoogle Scholar
  55. Schardin M, Cremer T, Hager HD, Lang M (1985) Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories. Hum Genet 71:281–287PubMedCrossRefGoogle Scholar
  56. Shelby RD, Vafa O, Sullivan KF (1997) Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites. J Cell Biol 136:501–513PubMedCrossRefGoogle Scholar
  57. Shortman K, Wu L (1996) Early T lymphocyte progenitors. Annu Rev Immunol 14:29–47PubMedCrossRefGoogle Scholar
  58. Singh H (1996) Gene targeting reveals a hierarchy of transcription factors regulating specification of lymphoid cell fates. Curr Opin Immunol 8:160–165PubMedCrossRefGoogle Scholar
  59. Smale ST, Fisher AG (2002) Chromatin structure and gene activation in the immune system. Ann Rev Immunol 20:427–462CrossRefGoogle Scholar
  60. Sullivan KF, Hechenberger M, Masri K (1994) Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere. J Cell Biol 127:581–592PubMedCrossRefGoogle Scholar
  61. Sun L, Heerema N, Crotty L, Wu X, Navara C, Vassilev A, Sensel M, Reaman GH, Uckun FM (1999) Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. Proc Natl Acad Sci 96:680–685PubMedCrossRefGoogle Scholar
  62. Sun L, Liu A, Georgopoulos K (1996) Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J 15:5358–5369PubMedGoogle Scholar
  63. Ting CN, Olson MC, Barton KP, Leiden JM (1996) Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384:474–478PubMedCrossRefGoogle Scholar
  64. Tomkiel J, Cooke CA, Saitoh H, Bernat RL, Earnshaw WC (1994) CENP-C is required for maintaining proper kinetochore size and for a timely transition to anaphase. J Cell Biol 125:531–545PubMedCrossRefGoogle Scholar
  65. Trinh LA, Ferrini R, Cobb BS, Weinmann AS, Hahm K, Ernst P, Garraway IP, Merkenschlager M, Smale ST (2001) Down-regulation of TDT transcription in CD4+CD8+ thymocytes by Ikaros proteins in direct competition with an Ets activator. Genes Dev 15:1817–1832PubMedCrossRefGoogle Scholar
  66. Vafa O, Sullivan KF (1997) Chromatin containing CENP-A and alpha-satellite DNA is a major component of the inner kinetochore plate. Curr Biol 7:897–900PubMedCrossRefGoogle Scholar
  67. Vissel B, Choo KH (1989) Mouse major (gamma) satellite DNA is highly conserved and organized into extremely long tandem arrays: implications for recombination between nonhomologous chromosomes. Genomics 5:407–414PubMedCrossRefGoogle Scholar
  68. Wang J, Avitahl N, Cariappa A, Friedrich C, Ikeda T, Renold A, Andrikopoulos K, Liang L, Pillai S, Morgan B et al. (1998) Aiolos Regulates B cell activation and maturation to effector state. Immunity 9:543–553PubMedCrossRefGoogle Scholar
  69. Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, Bigby M, Georgopoulos K (1996) Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5:537–549PubMedCrossRefGoogle Scholar
  70. Wansink DG, Sibon OC, Cremers FF, van Driel R, de Jong L (1996) Ultrastructural localization of active genes in nuclei of A431 cells. J Cell Biochem 62:10–18PubMedCrossRefGoogle Scholar
  71. Warburton PE, Cooke CA, Bourassa S, Vafa O, Sullivan BA, Stetten G, Gimelli G, Warburton D, Tyler-Smith C, Sullivan KF et al. (1997) Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres. Curr Biol 7:901–904PubMedCrossRefGoogle Scholar
  72. Westman BJ, Perdomo, J, Sunde M, Crossley M, Mackay JP (2003) The C-terminal domain of Eos forms a high order complex in solution. J Biol Chem 278:42419–42426PubMedCrossRefGoogle Scholar
  73. Wiens GR, Sorger PK (1998) Centromeric chromatin and epigenetic effects in kinetochore assembly. Cell 93:313–316PubMedCrossRefGoogle Scholar
  74. Winandy S, Wu P, Georgopoulos K (1995) A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 83:289–299PubMedCrossRefGoogle Scholar
  75. Winandy S, Wu L, Wang JH, Georgopoulos K (1999) Pre-T cell receptor (TCR) TCR-controlled checkpoints in T cell differentiation are set by Ikaros. J Exp Med 190:1039–1048PubMedCrossRefGoogle Scholar
  76. Wong AK, Rattner JB (1988) Sequence organization and cytological localization of the minor satellite of mouse. Nucleic Acids Res 16:11645–11661PubMedGoogle Scholar
  77. Wu L, Nichogiannopoulou A, Shortman K, Georgopoulos K (1997) Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity 7:483–492PubMedCrossRefGoogle Scholar
  78. Yen TJ, Compton DA, Wise D, Zinkowski RP, Brinkley BR, Earnshaw WC, Cleveland DW (1991) CENP-E, a novel human centromere-associated protein required for progression from metaphase to anaphase. EMBO J 10:1245–1254PubMedGoogle Scholar
  79. Zhang CC, Bienz M (1992) Segmental determination in Drosophila conferred by hunchback (hb), a repressor of the homeotic gene Ultrabithorax (Ubx). Proc Natl Acad Sci U S A 89:7511–7515PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • B. S. Cobb
    • 1
  • S. T. Smale
    • 1
  1. 1.Department of Microbiology, Immunology and Molecular Genetics, Howard Hughes Medical InstituteUniversity of CaliforniaLos AngelesUSA

Personalised recommendations