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. 1999 Jun 1;18(11):3090–3100. doi: 10.1093/emboj/18.11.3090

Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes.

J Koipally 1, A Renold 1, J Kim 1, K Georgopoulos 1
PMCID: PMC1171390  PMID: 10357820

Abstract

Here we show that the lymphoid lineage-determining factors Ikaros and Aiolos can function as strong transcriptional repressors. This function is mediated through two repression domains and is dependent upon the promoter context and cell type. Repression by Ikaros proteins correlates with hypo-acetylation of core histones at promoter sites and is relieved by histone deacetylase inhibitors. Consistent with these findings, Ikaros and its repression domains can interact in vivo and in vitro with the mSin3 family of co-repressors which bind to histone deacetylases. Based on these and our recent findings of associations between Ikaros and Mi-2-HDAC, we propose that Ikaros family members modulate gene expression during lymphocyte development by recruiting distinct histone deacetylase complexes to specific promoters.

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Selected References

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  1. Alland L., Muhle R., Hou H., Jr, Potes J., Chin L., Schreiber-Agus N., DePinho R. A. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature. 1997 May 1;387(6628):49–55. doi: 10.1038/387049a0. [DOI] [PubMed] [Google Scholar]
  2. Avitahl N., Winandy S., Friedrich C., Jones B., Ge Y., Georgopoulos K. Ikaros sets thresholds for T cell activation and regulates chromosome propagation. Immunity. 1999 Mar;10(3):333–343. doi: 10.1016/s1074-7613(00)80033-3. [DOI] [PubMed] [Google Scholar]
  3. Ayer D. E., Laherty C. D., Lawrence Q. A., Armstrong A. P., Eisenman R. N. Mad proteins contain a dominant transcription repression domain. Mol Cell Biol. 1996 Oct;16(10):5772–5781. doi: 10.1128/mcb.16.10.5772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ayer D. E., Lawrence Q. A., Eisenman R. N. Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell. 1995 Mar 10;80(5):767–776. doi: 10.1016/0092-8674(95)90355-0. [DOI] [PubMed] [Google Scholar]
  5. Bowdish K. S., Yuan H. E., Mitchell A. P. Positive control of yeast meiotic genes by the negative regulator UME6. Mol Cell Biol. 1995 Jun;15(6):2955–2961. doi: 10.1128/mcb.15.6.2955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brown K. E., Guest S. S., Smale S. T., Hahm K., Merkenschlager M., Fisher A. G. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell. 1997 Dec 12;91(6):845–854. doi: 10.1016/s0092-8674(00)80472-9. [DOI] [PubMed] [Google Scholar]
  7. Carmen A. A., Rundlett S. E., Grunstein M. HDA1 and HDA3 are components of a yeast histone deacetylase (HDA) complex. J Biol Chem. 1996 Jun 28;271(26):15837–15844. doi: 10.1074/jbc.271.26.15837. [DOI] [PubMed] [Google Scholar]
  8. Cortes M., Wong E., Koipally J., Georgopoulos K. Control of lymphocyte development by the Ikaros gene family. Curr Opin Immunol. 1999 Apr;11(2):167–171. doi: 10.1016/s0952-7915(99)80028-4. [DOI] [PubMed] [Google Scholar]
  9. Ekwall K., Olsson T., Turner B. M., Cranston G., Allshire R. C. Transient inhibition of histone deacetylation alters the structural and functional imprint at fission yeast centromeres. Cell. 1997 Dec 26;91(7):1021–1032. doi: 10.1016/s0092-8674(00)80492-4. [DOI] [PubMed] [Google Scholar]
  10. Gelmetti V., Zhang J., Fanelli M., Minucci S., Pelicci P. G., Lazar M. A. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol. 1998 Dec;18(12):7185–7191. doi: 10.1128/mcb.18.12.7185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Georgopoulos K., Bigby M., Wang J. H., Molnar A., Wu P., Winandy S., Sharpe A. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994 Oct 7;79(1):143–156. doi: 10.1016/0092-8674(94)90407-3. [DOI] [PubMed] [Google Scholar]
  12. Georgopoulos K., Moore D. D., Derfler B. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science. 1992 Oct 30;258(5083):808–812. doi: 10.1126/science.1439790. [DOI] [PubMed] [Google Scholar]
  13. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997 Sep 25;389(6649):349–352. doi: 10.1038/38664. [DOI] [PubMed] [Google Scholar]
  14. Hahm K., Cobb B. S., McCarty A. S., Brown K. E., Klug C. A., Lee R., Akashi K., Weissman I. L., Fisher A. G., Smale S. T. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes Dev. 1998 Mar 15;12(6):782–796. doi: 10.1101/gad.12.6.782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hahm K., Ernst P., Lo K., Kim G. S., Turck C., Smale S. T. The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene. Mol Cell Biol. 1994 Nov;14(11):7111–7123. doi: 10.1128/mcb.14.11.7111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hassig C. A., Schreiber S. L. Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs. Curr Opin Chem Biol. 1997 Oct;1(3):300–308. doi: 10.1016/s1367-5931(97)80066-x. [DOI] [PubMed] [Google Scholar]
  17. Hsieh J. J., Zhou S., Chen L., Young D. B., Hayward S. D. CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):23–28. doi: 10.1073/pnas.96.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jeppesen P. Histone acetylation: a possible mechanism for the inheritance of cell memory at mitosis. Bioessays. 1997 Jan;19(1):67–74. doi: 10.1002/bies.950190111. [DOI] [PubMed] [Google Scholar]
  19. Kadosh D., Struhl K. Targeted recruitment of the Sin3-Rpd3 histone deacetylase complex generates a highly localized domain of repressed chromatin in vivo. Mol Cell Biol. 1998 Sep;18(9):5121–5127. doi: 10.1128/mcb.18.9.5121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kao H. Y., Ordentlich P., Koyano-Nakagawa N., Tang Z., Downes M., Kintner C. R., Evans R. M., Kadesch T. A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev. 1998 Aug 1;12(15):2269–2277. doi: 10.1101/gad.12.15.2269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kasten M. M., Ayer D. E., Stillman D. J. SIN3-dependent transcriptional repression by interaction with the Mad1 DNA-binding protein. Mol Cell Biol. 1996 Aug;16(8):4215–4221. doi: 10.1128/mcb.16.8.4215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kelley C. M., Ikeda T., Koipally J., Avitahl N., Wu L., Georgopoulos K., Morgan B. A. Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Curr Biol. 1998 Apr 23;8(9):508–515. doi: 10.1016/s0960-9822(98)70202-7. [DOI] [PubMed] [Google Scholar]
  23. Kim J., Sif S., Jones B., Jackson A., Koipally J., Heller E., Winandy S., Viel A., Sawyer A., Ikeda T. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999 Mar;10(3):345–355. doi: 10.1016/s1074-7613(00)80034-5. [DOI] [PubMed] [Google Scholar]
  24. Klug C. A., Morrison S. J., Masek M., Hahm K., Smale S. T., Weissman I. L. Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):657–662. doi: 10.1073/pnas.95.2.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kuo M. H., Allis C. D. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays. 1998 Aug;20(8):615–626. doi: 10.1002/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  26. Kölle D., Brosch G., Lechner T., Lusser A., Loidl P. Biochemical methods for analysis of histone deacetylases. Methods. 1998 Aug;15(4):323–331. doi: 10.1006/meth.1998.0636. [DOI] [PubMed] [Google Scholar]
  27. Lin R. J., Nagy L., Inoue S., Shao W., Miller W. H., Jr, Evans R. M. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 1998 Feb 19;391(6669):811–814. doi: 10.1038/35895. [DOI] [PubMed] [Google Scholar]
  28. Luo R. X., Postigo A. A., Dean D. C. Rb interacts with histone deacetylase to repress transcription. Cell. 1998 Feb 20;92(4):463–473. doi: 10.1016/s0092-8674(00)80940-x. [DOI] [PubMed] [Google Scholar]
  29. Morgan B., Sun L., Avitahl N., Andrikopoulos K., Ikeda T., Gonzales E., Wu P., Neben S., Georgopoulos K. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 1997 Apr 15;16(8):2004–2013. doi: 10.1093/emboj/16.8.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rundlett S. E., Carmen A. A., Kobayashi R., Bavykin S., Turner B. M., Grunstein M. HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14503–14508. doi: 10.1073/pnas.93.25.14503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schreiber-Agus N., Chin L., Chen K., Torres R., Rao G., Guida P., Skoultchi A. I., DePinho R. A. An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell. 1995 Mar 10;80(5):777–786. doi: 10.1016/0092-8674(95)90356-9. [DOI] [PubMed] [Google Scholar]
  32. Schreiber-Agus N., DePinho R. A. Repression by the Mad(Mxi1)-Sin3 complex. Bioessays. 1998 Oct;20(10):808–818. doi: 10.1002/(SICI)1521-1878(199810)20:10<808::AID-BIES6>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  33. Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 1998 Mar 1;12(5):599–606. doi: 10.1101/gad.12.5.599. [DOI] [PubMed] [Google Scholar]
  34. Sun L., Heerema N., Crotty L., Wu X., Navara C., Vassilev A., Sensel M., Reaman G. H., Uckun F. M. Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):680–685. doi: 10.1073/pnas.96.2.680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sun L., Liu A., Georgopoulos K. Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J. 1996 Oct 1;15(19):5358–5369. [PMC free article] [PubMed] [Google Scholar]
  36. Tong J. K., Hassig C. A., Schnitzler G. R., Kingston R. E., Schreiber S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature. 1998 Oct 29;395(6705):917–921. doi: 10.1038/27699. [DOI] [PubMed] [Google Scholar]
  37. Torchia J., Glass C., Rosenfeld M. G. Co-activators and co-repressors in the integration of transcriptional responses. Curr Opin Cell Biol. 1998 Jun;10(3):373–383. doi: 10.1016/s0955-0674(98)80014-8. [DOI] [PubMed] [Google Scholar]
  38. Wade P. A., Jones P. L., Vermaak D., Wolffe A. P. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr Biol. 1998 Jul 2;8(14):843–846. doi: 10.1016/s0960-9822(98)70328-8. [DOI] [PubMed] [Google Scholar]
  39. Wang H., Stillman D. J. Transcriptional repression in Saccharomyces cerevisiae by a SIN3-LexA fusion protein. Mol Cell Biol. 1993 Mar;13(3):1805–1814. doi: 10.1128/mcb.13.3.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wang J. H., Avitahl N., Cariappa A., Friedrich C., Ikeda T., Renold A., Andrikopoulos K., Liang L., Pillai S., Morgan B. A. Aiolos regulates B cell activation and maturation to effector state. Immunity. 1998 Oct;9(4):543–553. doi: 10.1016/s1074-7613(00)80637-8. [DOI] [PubMed] [Google Scholar]
  41. Wang J. H., Nichogiannopoulou A., Wu L., Sun L., Sharpe A. H., Bigby M., Georgopoulos K. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity. 1996 Dec;5(6):537–549. doi: 10.1016/s1074-7613(00)80269-1. [DOI] [PubMed] [Google Scholar]
  42. Wang J., Hoshino T., Redner R. L., Kajigaya S., Liu J. M. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10860–10865. doi: 10.1073/pnas.95.18.10860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wargnier A., Lafaurie C., Legros-Maïda S., Bourge J. F., Sigaux F., Sasportes M., Paul P. Down-regulation of human granzyme B expression by glucocorticoids. Dexamethasone inhibits binding to the Ikaros and AP-1 regulatory elements of the granzyme B promoter. J Biol Chem. 1998 Dec 25;273(52):35326–35331. doi: 10.1074/jbc.273.52.35326. [DOI] [PubMed] [Google Scholar]
  44. Winandy S., Wu P., Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995 Oct 20;83(2):289–299. doi: 10.1016/0092-8674(95)90170-1. [DOI] [PubMed] [Google Scholar]
  45. Workman J. L., Kingston R. E. Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu Rev Biochem. 1998;67:545–579. doi: 10.1146/annurev.biochem.67.1.545. [DOI] [PubMed] [Google Scholar]
  46. Xue Y., Wong J., Moreno G. T., Young M. K., Côté J., Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell. 1998 Dec;2(6):851–861. doi: 10.1016/s1097-2765(00)80299-3. [DOI] [PubMed] [Google Scholar]
  47. Yang W. M., Inouye C., Zeng Y., Bearss D., Seto E. Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12845–12850. doi: 10.1073/pnas.93.23.12845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Zhang Y., LeRoy G., Seelig H. P., Lane W. S., Reinberg D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell. 1998 Oct 16;95(2):279–289. doi: 10.1016/s0092-8674(00)81758-4. [DOI] [PubMed] [Google Scholar]

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