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.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
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 10:333–343
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 111:1519–1533
Bernat RL, Delannoy MR, Rothfield NF, Earnshaw WC (1991) Disruption of centromere assembly during interphase inhibits kinetochore morphogenesis and function in mitosis. Cell 66:1229–1238
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 91:845–854
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 3:207–217
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 19:1179–1182
Clevers HC, Grosschedl R (1996) Transcriptional control of lymphoid development: lessons from gene targeting. Immunol Today 17:336–343
Clevers HC, Oosterwegel MA, Georgopoulos K (1993) Transcription factors in early T-cell development. Immunol Today 14:591–596
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 14:2146–2160
Cortes M, Wong E, Koipally J, Georgopoulos K (1999) Control of lymphocyte development by the Ikaros gene family. Curr Op Immunol 11:167–171
Csink AK, Henikoff S (1998) Something from nothing: the evolution and utility of satellite repeats. Trends Genet 14:200–204
Dumortier A, Kirstetter P, Kastner P, Chan S (2003) Ikaros regulates neutrophil differentiation. Blood 101:2219–2226
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 13:2982–2992
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 16:6121–6131
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 139:1597–1610
Georgopoulos K (1997) Transcription factors required for lymphoid lineage commitment. Curr Opin Immunol 9:222–227
Georgopoulos K (2002) Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nature Rev Immunol 2:162–174
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 79:143–156
Georgopoulos K, Moore DD, Derfler B (1992) Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science 258:808–812
Georgopoulos K, Winandy S, Avitahl N (1997) The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol 15:155–176
Glimcher LH, Singh H (1999) Transcription factors in lymphocyte development—T B cells get together. Cell 96:13–23
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 12:782–796
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 14:7111–7123
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 27:3049–3058
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 10:1403–1415
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 447:76–80
Karpen GH, Allshire RC (1997) The case for epigenetic effects on centromere identity and function. Trends Genet 13:489–496
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 8:508–515
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 10:345–355
Kipling D, Warburton PE (1997) Centromeres, CENP-B Tigger too. Trends Genet 13:141–145
Kirstetter P, Thomas M, Dierich A, Kastner P, Chan S (2002) Ikaros is critical for B cell differentiation and function. Eur J Immunol 32:720–730
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 95:657–662
Koipally J, Renold A, Kim J, Georgopoulos K (1999) Repression by Ikaros Aiolos is mediated through histone deacetylase complexes. EMBO J 18:3090–3100
Koipally J, Georgopoulos K (2000) Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity. J Biol Chem 275:19594–19602
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 135:1195–1205
Lamond AI, Earnshaw WC (1998) Structure and function in the nucleus. Science 280:547–553
Liippo J, Lassila O (1997) Avian Ikaros gene is expressed early in embryogenesis. Eur J Immunol 27:1853–1857
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 11:5229–5243
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 181:181–196
McCarty AS, Kleiger G, Eisenberg D, Smale ST (2003) Selective dimerization of a C2H2 zinc finger subfamily. Mol Cell 11:459–470
MolnQr A, Georgopoulos K (1994) The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol 14:8292–8303
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 156:585–592
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 16:2004–2013
Murphy TD, Karpen GH (1998) Centromeres take flight: alpha satellite and the quest for the human centromere. Cell 93:317–320
Nichogiannopoulou A, Trevisan M, Friedrich C, Georgopoulos K (1998) Ikaros in hemopoietic lineage determination and homeostasis. Semin Immunol 10:119–125
Nichogiannopoulou A, Trevisan M, Neben S, Friedrich C, Georgopoulos K (1999) Defects in hemopoietic stem cell activity in Ikaros mutant mice. J Exp Med 190:1201–1214
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 14:3946–3957
Orkin SH (1995) Hematopoiesis: how does it happen? Curr Opin Cell Biol 7:870–877
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 19:131–144
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 275:38347–38354
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 140:1297–1306
Pluta AF, Mackay AM, Ainsztein AM, Goldberg IG, Earnshaw WC (1995) The centromere: hub of chromosomal activities. Science 270:1591–1594
Poux S, Kostic C, Pirrotta V (1996) Hunchback-independent silencing of late Ubx enhancers by a Polycomb Group Response Element. EMBO J 15:4713–4722
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 20:2812–2822
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 71:281–287
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 136:501–513
Shortman K, Wu L (1996) Early T lymphocyte progenitors. Annu Rev Immunol 14:29–47
Singh H (1996) Gene targeting reveals a hierarchy of transcription factors regulating specification of lymphoid cell fates. Curr Opin Immunol 8:160–165
Smale ST, Fisher AG (2002) Chromatin structure and gene activation in the immune system. Ann Rev Immunol 20:427–462
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 127:581–592
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 96:680–685
Sun L, Liu A, Georgopoulos K (1996) Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J 15:5358–5369
Ting CN, Olson MC, Barton KP, Leiden JM (1996) Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384:474–478
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 125:531–545
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 15:1817–1832
Vafa O, Sullivan KF (1997) Chromatin containing CENP-A and alpha-satellite DNA is a major component of the inner kinetochore plate. Curr Biol 7:897–900
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 5:407–414
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 9:543–553
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 5:537–549
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 62:10–18
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 7:901–904
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 278:42419–42426
Wiens GR, Sorger PK (1998) Centromeric chromatin and epigenetic effects in kinetochore assembly. Cell 93:313–316
Winandy S, Wu P, Georgopoulos K (1995) A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 83:289–299
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 190:1039–1048
Wong AK, Rattner JB (1988) Sequence organization and cytological localization of the minor satellite of mouse. Nucleic Acids Res 16:11645–11661
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 7:483–492
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 10:1245–1254
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 89:7511–7515
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer-Verlag
About this chapter
Cite this chapter
Cobb, B.S., Smale, S.T. (2005). Ikaros-Family Proteins: In Search of Molecular Functions During Lymphocyte Development. In: Singh, H., Grosschedl, R. (eds) Molecular Analysis of B Lymphocyte Development and Activation. Current Topics in Microbiology and Immunology, vol 290. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26363-2_3
Download citation
DOI: https://doi.org/10.1007/3-540-26363-2_3
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-23090-8
Online ISBN: 978-3-540-26363-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)