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. 1998 Oct 1;17(19):5734–5743. doi: 10.1093/emboj/17.19.5734

Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer.

A Muto 1, H Hoshino 1, L Madisen 1, N Yanai 1, M Obinata 1, H Karasuyama 1, N Hayashi 1, H Nakauchi 1, M Yamamoto 1, M Groudine 1, K Igarashi 1
PMCID: PMC1170901  PMID: 9755173

Abstract

Maf family transcription factors are important regulators in various differentiation systems. Putative Maf recognition elements (MAREs) are found in the 3' enhancer region of the immunoglobulin heavy chain (IgH) gene. These elements are bound in B-cell extracts by a heterodimeric protein complex containing both Bach2 and a small Maf protein. Analysis of normal hematopoietic cells revealed that Bach2 is specifically expressed in B cells. Bach2 is abundantly expressed in the early stages of B-cell differentiation and turned off in terminally differentiated cells. Bach2 acts together with MafK as a negative effector of the IgH 3' enhancer and binds to the co-repressor SMRT (silencing mediator of retinoid and thyroid receptor). Hence the Bach2-small-Maf heterodimer may represent the first example of a B-cell lineage, and of a developmental stage-restricted negative effector of the MARE in the IgH 3' enhancer region.

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Selected References

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  1. Albagli O., Dhordain P., Deweindt C., Lecocq G., Leprince D. The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins. Cell Growth Differ. 1995 Sep;6(9):1193–1198. [PubMed] [Google Scholar]
  2. Alt F., Rosenberg N., Lewis S., Thomas E., Baltimore D. Organization and reorganization of immunoglobulin genes in A-MULV-transformed cells: rearrangement of heavy but not light chain genes. Cell. 1981 Dec;27(2 Pt 1):381–390. doi: 10.1016/0092-8674(81)90421-9. [DOI] [PubMed] [Google Scholar]
  3. Amati B., Land H. Myc-Max-Mad: a transcription factor network controlling cell cycle progression, differentiation and death. Curr Opin Genet Dev. 1994 Feb;4(1):102–108. doi: 10.1016/0959-437x(94)90098-1. [DOI] [PubMed] [Google Scholar]
  4. Andrews N. C., Erdjument-Bromage H., Davidson M. B., Tempst P., Orkin S. H. Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature. 1993 Apr 22;362(6422):722–728. doi: 10.1038/362722a0. [DOI] [PubMed] [Google Scholar]
  5. Andrews N. C., Faller D. V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 1991 May 11;19(9):2499–2499. doi: 10.1093/nar/19.9.2499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Andrews N. C., Kotkow K. J., Ney P. A., Erdjument-Bromage H., Tempst P., Orkin S. H. The ubiquitous subunit of erythroid transcription factor NF-E2 is a small basic-leucine zipper protein related to the v-maf oncogene. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11488–11492. doi: 10.1073/pnas.90.24.11488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Arulampalam V., Eckhardt L., Pettersson S. The enhancer shift: a model to explain the developmental control of IgH gene expression in B-lineage cells. Immunol Today. 1997 Nov;18(11):549–554. doi: 10.1016/s0167-5699(97)01154-7. [DOI] [PubMed] [Google Scholar]
  8. Barberis A., Widenhorn K., Vitelli L., Busslinger M. A novel B-cell lineage-specific transcription factor present at early but not late stages of differentiation. Genes Dev. 1990 May;4(5):849–859. doi: 10.1101/gad.4.5.849. [DOI] [PubMed] [Google Scholar]
  9. Blank V., Andrews N. C. The Maf transcription factors: regulators of differentiation. Trends Biochem Sci. 1997 Nov;22(11):437–441. doi: 10.1016/s0968-0004(97)01105-5. [DOI] [PubMed] [Google Scholar]
  10. Blank V., Kim M. J., Andrews N. C. Human MafG is a functional partner for p45 NF-E2 in activating globin gene expression. Blood. 1997 Jun 1;89(11):3925–3935. [PubMed] [Google Scholar]
  11. 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]
  12. Caterina J. J., Donze D., Sun C. W., Ciavatta D. J., Townes T. M. Cloning and functional characterization of LCR-F1: a bZIP transcription factor that activates erythroid-specific, human globin gene expression. Nucleic Acids Res. 1994 Jun 25;22(12):2383–2391. doi: 10.1093/nar/22.12.2383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chan J. Y., Han X. L., Kan Y. W. Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11371–11375. doi: 10.1073/pnas.90.23.11371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chauveau C., Cogné M. Palindromic structure of the IgH 3'locus control region. Nat Genet. 1996 Sep;14(1):15–16. doi: 10.1038/ng0996-15. [DOI] [PubMed] [Google Scholar]
  15. Chen Z., Brand N. J., Chen A., Chen S. J., Tong J. H., Wang Z. Y., Waxman S., Zelent A. Fusion between a novel Krüppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J. 1993 Mar;12(3):1161–1167. doi: 10.1002/j.1460-2075.1993.tb05757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dhordain P., Albagli O., Lin R. J., Ansieau S., Quief S., Leutz A., Kerckaert J. P., Evans R. M., Leprince D. Corepressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10762–10767. doi: 10.1073/pnas.94.20.10762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Engel J. D. Meticulous AP-1 factors. Nature. 1994 Feb 10;367(6463):516–517. doi: 10.1038/367516a0. [DOI] [PubMed] [Google Scholar]
  18. Fitzsimmons D., Hagman J. Regulation of gene expression at early stages of B-cell and T-cell differentiation. Curr Opin Immunol. 1996 Apr;8(2):166–174. doi: 10.1016/s0952-7915(96)80054-9. [DOI] [PubMed] [Google Scholar]
  19. Fujiwara K. T., Kataoka K., Nishizawa M. Two new members of the maf oncogene family, mafK and mafF, encode nuclear b-Zip proteins lacking putative trans-activator domain. Oncogene. 1993 Sep;8(9):2371–2380. [PubMed] [Google Scholar]
  20. Georgopoulos K. Transcription factors required for lymphoid lineage commitment. Curr Opin Immunol. 1997 Apr;9(2):222–227. doi: 10.1016/s0952-7915(97)80139-2. [DOI] [PubMed] [Google Scholar]
  21. Grant P. A., Thompson C. B., Pettersson S. IgM receptor-mediated transactivation of the IgH 3' enhancer couples a novel Elf-1-AP-1 protein complex to the developmental control of enhancer function. EMBO J. 1995 Sep 15;14(18):4501–4513. doi: 10.1002/j.1460-2075.1995.tb00129.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Grignani F., De Matteis S., Nervi C., Tomassoni L., Gelmetti V., Cioce M., Fanelli M., Ruthardt M., Ferrara F. F., Zamir I. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. 1998 Feb 19;391(6669):815–818. doi: 10.1038/35901. [DOI] [PubMed] [Google Scholar]
  23. Hagman J., Belanger C., Travis A., Turck C. W., Grosschedl R. Cloning and functional characterization of early B-cell factor, a regulator of lymphocyte-specific gene expression. Genes Dev. 1993 May;7(5):760–773. doi: 10.1101/gad.7.5.760. [DOI] [PubMed] [Google Scholar]
  24. Hardy R. R., Carmack C. E., Shinton S. A., Kemp J. D., Hayakawa K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med. 1991 May 1;173(5):1213–1225. doi: 10.1084/jem.173.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hardy R. R., Dangl J. L., Hayakawa K., Jager G., Herzenberg L. A., Herzenberg L. A. Frequent lambda light chain gene rearrangement and expression in a Ly-1 B lymphoma with a productive kappa chain allele. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1438–1442. doi: 10.1073/pnas.83.5.1438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ho I. C., Hodge M. R., Rooney J. W., Glimcher L. H. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell. 1996 Jun 28;85(7):973–983. doi: 10.1016/s0092-8674(00)81299-4. [DOI] [PubMed] [Google Scholar]
  27. Hu M., Krause D., Greaves M., Sharkis S., Dexter M., Heyworth C., Enver T. Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 1997 Mar 15;11(6):774–785. doi: 10.1101/gad.11.6.774. [DOI] [PubMed] [Google Scholar]
  28. Igarashi K., Hoshino H., Muto A., Suwabe N., Nishikawa S., Nakauchi H., Yamamoto M. Multivalent DNA binding complex generated by small Maf and Bach1 as a possible biochemical basis for beta-globin locus control region complex. J Biol Chem. 1998 May 8;273(19):11783–11790. doi: 10.1074/jbc.273.19.11783. [DOI] [PubMed] [Google Scholar]
  29. Igarashi K., Itoh K., Hayashi N., Nishizawa M., Yamamoto M. Conditional expression of the ubiquitous transcription factor MafK induces erythroleukemia cell differentiation. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7445–7449. doi: 10.1073/pnas.92.16.7445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Igarashi K., Itoh K., Motohashi H., Hayashi N., Matuzaki Y., Nakauchi H., Nishizawa M., Yamamoto M. Activity and expression of murine small Maf family protein MafK. J Biol Chem. 1995 Mar 31;270(13):7615–7624. doi: 10.1074/jbc.270.13.7615. [DOI] [PubMed] [Google Scholar]
  31. Igarashi K., Kataoka K., Itoh K., Hayashi N., Nishizawa M., Yamamoto M. Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins. Nature. 1994 Feb 10;367(6463):568–572. doi: 10.1038/367568a0. [DOI] [PubMed] [Google Scholar]
  32. Itoh K., Igarashi K., Hayashi N., Nishizawa M., Yamamoto M. Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol Cell Biol. 1995 Aug;15(8):4184–4193. doi: 10.1128/mcb.15.8.4184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Johnsen O., Murphy P., Prydz H., Kolsto A. B. Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription. Nucleic Acids Res. 1998 Jan 15;26(2):512–520. doi: 10.1093/nar/26.2.512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kataoka K., Fujiwara K. T., Noda M., Nishizawa M. MafB, a new Maf family transcription activator that can associate with Maf and Fos but not with Jun. Mol Cell Biol. 1994 Nov;14(11):7581–7591. doi: 10.1128/mcb.14.11.7581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kataoka K., Igarashi K., Itoh K., Fujiwara K. T., Noda M., Yamamoto M., Nishizawa M. Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NF-E2 transcription factor. Mol Cell Biol. 1995 Apr;15(4):2180–2190. doi: 10.1128/mcb.15.4.2180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kataoka K., Nishizawa M., Kawai S. Structure-function analysis of the maf oncogene product, a member of the b-Zip protein family. J Virol. 1993 Apr;67(4):2133–2141. doi: 10.1128/jvi.67.4.2133-2141.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kataoka K., Noda M., Nishizawa M. Maf nuclear oncoprotein recognizes sequences related to an AP-1 site and forms heterodimers with both Fos and Jun. Mol Cell Biol. 1994 Jan;14(1):700–712. doi: 10.1128/mcb.14.1.700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kearney J. F., Radbruch A., Liesegang B., Rajewsky K. A new mouse myeloma cell line that has lost immunoglobulin expression but permits the construction of antibody-secreting hybrid cell lines. J Immunol. 1979 Oct;123(4):1548–1550. [PubMed] [Google Scholar]
  39. Kim K. J., Kanellopoulos-Langevin C., Merwin R. M., Sachs D. H., Asofsky R. Establishment and characterization of BALB/c lymphoma lines with B cell properties. J Immunol. 1979 Feb;122(2):549–554. [PubMed] [Google Scholar]
  40. Koguma M., Matsuda K., Okuyama R., Yanai N., Obinata M. Selective proliferation of lymphoid cells from lineage-c-Kit+ Sca-1+ cells by a clonal bone marrow stromal cell line. Exp Hematol. 1998 Apr;26(4):280–287. [PubMed] [Google Scholar]
  41. Li Y. S., Wasserman R., Hayakawa K., Hardy R. R. Identification of the earliest B lineage stage in mouse bone marrow. Immunity. 1996 Dec;5(6):527–535. doi: 10.1016/s1074-7613(00)80268-x. [DOI] [PubMed] [Google Scholar]
  42. Lieberson R., Giannini S. L., Birshtein B. K., Eckhardt L. A. An enhancer at the 3' end of the mouse immunoglobulin heavy chain locus. Nucleic Acids Res. 1991 Feb 25;19(4):933–937. doi: 10.1093/nar/19.4.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. 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]
  44. Luna L., Johnsen O., Skartlien A. H., Pedeutour F., Turc-Carel C., Prydz H., Kolstø A. B. Molecular cloning of a putative novel human bZIP transcription factor on chromosome 17q22. Genomics. 1994 Aug;22(3):553–562. doi: 10.1006/geno.1994.1428. [DOI] [PubMed] [Google Scholar]
  45. Lynes M. A., Lanier L. L., Babcock G. F., Wettstein P. J., Haughton G. Antigen-induced murine B cell lymphomas. I. Induction and characterization of CH1 and CH2. J Immunol. 1978 Dec;121(6):2352–2357. [PubMed] [Google Scholar]
  46. Madisen L., Groudine M. Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells. Genes Dev. 1994 Sep 15;8(18):2212–2226. doi: 10.1101/gad.8.18.2212. [DOI] [PubMed] [Google Scholar]
  47. Matthias P., Baltimore D. The immunoglobulin heavy chain locus contains another B-cell-specific 3' enhancer close to the alpha constant region. Mol Cell Biol. 1993 Mar;13(3):1547–1553. doi: 10.1128/mcb.13.3.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Mills F. C., Harindranath N., Mitchell M., Max E. E. Enhancer complexes located downstream of both human immunoglobulin Calpha genes. J Exp Med. 1997 Sep 15;186(6):845–858. doi: 10.1084/jem.186.6.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Moi P., Chan K., Asunis I., Cao A., Kan Y. W. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9926–9930. doi: 10.1073/pnas.91.21.9926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Motohashi H., Igarashi K., Onodera K., Takahashi S., Ohtani H., Nakafuku M., Nishizawa M., Engel J. D., Yamamoto M. Mesodermal- vs. neuronal-specific expression of MafK is elicited by different promoters. Genes Cells. 1996 Feb;1(2):223–238. doi: 10.1046/j.1365-2443.1996.d01-230.x. [DOI] [PubMed] [Google Scholar]
  51. Motohashi H., Shavit J. A., Igarashi K., Yamamoto M., Engel J. D. The world according to Maf. Nucleic Acids Res. 1997 Aug 1;25(15):2953–2959. doi: 10.1093/nar/25.15.2953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Ney P. A., Andrews N. C., Jane S. M., Safer B., Purucker M. E., Weremowicz S., Morton C. C., Goff S. C., Orkin S. H., Nienhuis A. W. Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic cell-specific subunit and evidence for an associated partner. Mol Cell Biol. 1993 Sep;13(9):5604–5612. doi: 10.1128/mcb.13.9.5604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Nishizawa M., Kataoka K., Goto N., Fujiwara K. T., Kawai S. v-maf, a viral oncogene that encodes a "leucine zipper" motif. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7711–7715. doi: 10.1073/pnas.86.20.7711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Oi V. T., Morrison S. L., Herzenberg L. A., Berg P. Immunoglobulin gene expression in transformed lymphoid cells. Proc Natl Acad Sci U S A. 1983 Feb;80(3):825–829. doi: 10.1073/pnas.80.3.825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Osawa M., Hanada K., Hamada H., Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996 Jul 12;273(5272):242–245. doi: 10.1126/science.273.5272.242. [DOI] [PubMed] [Google Scholar]
  56. Oyake T., Itoh K., Motohashi H., Hayashi N., Hoshino H., Nishizawa M., Yamamoto M., Igarashi K. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol Cell Biol. 1996 Nov;16(11):6083–6095. doi: 10.1128/mcb.16.11.6083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Pagano M., Dürst M., Joswig S., Draetta G., Jansen-Dürr P. Binding of the human E2F transcription factor to the retinoblastoma protein but not to cyclin A is abolished in HPV-16-immortalized cells. Oncogene. 1992 Sep;7(9):1681–1686. [PubMed] [Google Scholar]
  58. Pettersson S., Cook G. P., Brüggemann M., Williams G. T., Neuberger M. S. A second B cell-specific enhancer 3' of the immunoglobulin heavy-chain locus. Nature. 1990 Mar 8;344(6262):165–168. doi: 10.1038/344165a0. [DOI] [PubMed] [Google Scholar]
  59. Rolink A., Melchers F. Molecular and cellular origins of B lymphocyte diversity. Cell. 1991 Sep 20;66(6):1081–1094. doi: 10.1016/0092-8674(91)90032-t. [DOI] [PubMed] [Google Scholar]
  60. Rosenberg N., Baltimore D. The effect of helper virus on Abelson virus-induced transformation of lymphoid cells. J Exp Med. 1978 Apr 1;147(4):1126–1141. doi: 10.1084/jem.147.4.1126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  62. Sibley C. H., Ewald S. J., Kehry M. R., Douglas R. H., Raschke W. C., Hood L. E. Characterization of multiple immunoglobulin mu-chains synthesized by two clones of a B cell lymphoma. J Immunol. 1980 Nov;125(5):2097–2105. [PubMed] [Google Scholar]
  63. Singh M., Birshtein B. K. NF-HB (BSAP) is a repressor of the murine immunoglobulin heavy-chain 3' alpha enhancer at early stages of B-cell differentiation. Mol Cell Biol. 1993 Jun;13(6):3611–3622. doi: 10.1128/mcb.13.6.3611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Swaroop A., Xu J. Z., Pawar H., Jackson A., Skolnick C., Agarwal N. A conserved retina-specific gene encodes a basic motif/leucine zipper domain. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):266–270. doi: 10.1073/pnas.89.1.266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Toki T., Itoh J., Kitazawa J., Arai K., Hatakeyama K., Akasaka J., Igarashi K., Nomura N., Yokoyama M., Yamamoto M. Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif. Oncogene. 1997 Apr 24;14(16):1901–1910. doi: 10.1038/sj.onc.1201024. [DOI] [PubMed] [Google Scholar]
  66. Warner N. L., Daley M. J., Richey J., Spellman C. Flow cytometry analysis of murine B cell lymphoma differentiation. Immunol Rev. 1979;48:197–243. doi: 10.1111/j.1600-065x.1979.tb00304.x. [DOI] [PubMed] [Google Scholar]
  67. Ye B. H., Lista F., Lo Coco F., Knowles D. M., Offit K., Chaganti R. S., Dalla-Favera R. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science. 1993 Oct 29;262(5134):747–750. doi: 10.1126/science.8235596. [DOI] [PubMed] [Google Scholar]

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