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. 1993 Mar;13(3):1547–1553. doi: 10.1128/mcb.13.3.1547

The immunoglobulin heavy chain locus contains another B-cell-specific 3' enhancer close to the alpha constant region.

P Matthias 1, D Baltimore 1
PMCID: PMC359466  PMID: 8441396

Abstract

The transcription of immunoglobulin genes is controlled by variable region promoters and by enhancers, both of which are lymphoid specific. Because immunoglobulin genes are subject to an extremely complex regulation, we anticipated that there might be additional control elements for these genes. We therefore sought additional enhancers and demonstrate here that there is indeed another weak transcriptional enhancer just 3' to the mouse alpha constant region. This novel immunoglobulin enhancer is lymphoid specific and at two positions can bind members of the Oct family of transcription factors.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alt F. W., Blackwell T. K., Yancopoulos G. D. Development of the primary antibody repertoire. Science. 1987 Nov 20;238(4830):1079–1087. doi: 10.1126/science.3317825. [DOI] [PubMed] [Google Scholar]
  2. Banerji J., Olson L., Schaffner W. A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell. 1983 Jul;33(3):729–740. doi: 10.1016/0092-8674(83)90015-6. [DOI] [PubMed] [Google Scholar]
  3. Blackwell T. K., Moore M. W., Yancopoulos G. D., Suh H., Lutzker S., Selsing E., Alt F. W. Recombination between immunoglobulin variable region gene segments is enhanced by transcription. Nature. 1986 Dec 11;324(6097):585–589. doi: 10.1038/324585a0. [DOI] [PubMed] [Google Scholar]
  4. Clerc R. G., Corcoran L. M., LeBowitz J. H., Baltimore D., Sharp P. A. The B-cell-specific Oct-2 protein contains POU box- and homeo box-type domains. Genes Dev. 1988 Dec;2(12A):1570–1581. doi: 10.1101/gad.2.12a.1570. [DOI] [PubMed] [Google Scholar]
  5. Dariavach P., Williams G. T., Campbell K., Pettersson S., Neuberger M. S. The mouse IgH 3'-enhancer. Eur J Immunol. 1991 Jun;21(6):1499–1504. doi: 10.1002/eji.1830210625. [DOI] [PubMed] [Google Scholar]
  6. Falkner F. G., Zachau H. G. Correct transcription of an immunoglobulin kappa gene requires an upstream fragment containing conserved sequence elements. Nature. 1984 Jul 5;310(5972):71–74. doi: 10.1038/310071a0. [DOI] [PubMed] [Google Scholar]
  7. Fletcher C., Heintz N., Roeder R. G. Purification and characterization of OTF-1, a transcription factor regulating cell cycle expression of a human histone H2b gene. Cell. 1987 Dec 4;51(5):773–781. doi: 10.1016/0092-8674(87)90100-0. [DOI] [PubMed] [Google Scholar]
  8. Franza B. R., Jr, Rauscher F. J., 3rd, Josephs S. F., Curran T. The Fos complex and Fos-related antigens recognize sequence elements that contain AP-1 binding sites. Science. 1988 Mar 4;239(4844):1150–1153. doi: 10.1126/science.2964084. [DOI] [PubMed] [Google Scholar]
  9. Gerster T., Matthias P., Thali M., Jiricny J., Schaffner W. Cell type-specificity elements of the immunoglobulin heavy chain gene enhancer. EMBO J. 1987 May;6(5):1323–1330. doi: 10.1002/j.1460-2075.1987.tb02371.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ghosh S., Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990 Apr 12;344(6267):678–682. doi: 10.1038/344678a0. [DOI] [PubMed] [Google Scholar]
  11. Gillies S. D., Morrison S. L., Oi V. T., Tonegawa S. A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell. 1983 Jul;33(3):717–728. doi: 10.1016/0092-8674(83)90014-4. [DOI] [PubMed] [Google Scholar]
  12. Gregor P. D., Morrison S. L. Myeloma mutant with a novel 3' flanking region: loss of normal sequence and insertion of repetitive elements leads to decreased transcription but normal processing of the alpha heavy-chain gene products. Mol Cell Biol. 1986 Jun;6(6):1903–1916. doi: 10.1128/mcb.6.6.1903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grosschedl R., Marx M. Stable propagation of the active transcriptional state of an immunoglobulin mu gene requires continuous enhancer function. Cell. 1988 Nov 18;55(4):645–654. doi: 10.1016/0092-8674(88)90223-1. [DOI] [PubMed] [Google Scholar]
  14. Hagman J., Rudin C. M., Haasch D., Chaplin D., Storb U. A novel enhancer in the immunoglobulin lambda locus is duplicated and functionally independent of NF kappa B. Genes Dev. 1990 Jun;4(6):978–992. doi: 10.1101/gad.4.6.978. [DOI] [PubMed] [Google Scholar]
  15. Kakkis E., Mercola M., Calame K. Strong transcriptional activation of translocated c-myc genes occurs without a strong nearby enhancer or promoter. Nucleic Acids Res. 1988 Jan 11;16(1):77–96. doi: 10.1093/nar/16.1.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kemler I., Schreiber E., Müller M. M., Matthias P., Schaffner W. Octamer transcription factors bind to two different sequence motifs of the immunoglobulin heavy chain promoter. EMBO J. 1989 Jul;8(7):2001–2008. doi: 10.1002/j.1460-2075.1989.tb03607.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Klein S., Sablitzky F., Radbruch A. Deletion of the IgH enhancer does not reduce immunoglobulin heavy chain production of a hybridoma IgD class switch variant. EMBO J. 1984 Nov;3(11):2473–2476. doi: 10.1002/j.1460-2075.1984.tb02158.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. LeBowitz J. H., Clerc R. G., Brenowitz M., Sharp P. A. The Oct-2 protein binds cooperatively to adjacent octamer sites. Genes Dev. 1989 Oct;3(10):1625–1638. doi: 10.1101/gad.3.10.1625. [DOI] [PubMed] [Google Scholar]
  19. Lenardo M., Pierce J. W., Baltimore D. Protein-binding sites in Ig gene enhancers determine transcriptional activity and inducibility. Science. 1987 Jun 19;236(4808):1573–1577. doi: 10.1126/science.3109035. [DOI] [PubMed] [Google Scholar]
  20. Lutzker S., Rothman P., Pollock R., Coffman R., Alt F. W. Mitogen- and IL-4-regulated expression of germ-line Ig gamma 2b transcripts: evidence for directed heavy chain class switching. Cell. 1988 Apr 22;53(2):177–184. doi: 10.1016/0092-8674(88)90379-0. [DOI] [PubMed] [Google Scholar]
  21. Meyer K. B., Neuberger M. S. The immunoglobulin kappa locus contains a second, stronger B-cell-specific enhancer which is located downstream of the constant region. EMBO J. 1989 Jul;8(7):1959–1964. doi: 10.1002/j.1460-2075.1989.tb03601.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Murre C., McCaw P. S., Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. doi: 10.1016/0092-8674(89)90682-x. [DOI] [PubMed] [Google Scholar]
  23. Murre C., Voronova A., Baltimore D. B-cell- and myocyte-specific E2-box-binding factors contain E12/E47-like subunits. Mol Cell Biol. 1991 Feb;11(2):1156–1160. doi: 10.1128/mcb.11.2.1156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Müller M. M., Ruppert S., Schaffner W., Matthias P. A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells. Nature. 1988 Dec 8;336(6199):544–551. doi: 10.1038/336544a0. [DOI] [PubMed] [Google Scholar]
  25. Parslow T. G., Blair D. L., Murphy W. J., Granner D. K. Structure of the 5' ends of immunoglobulin genes: a novel conserved sequence. Proc Natl Acad Sci U S A. 1984 May;81(9):2650–2654. doi: 10.1073/pnas.81.9.2650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Pierce J. W., Lenardo M., Baltimore D. Oligonucleotide that binds nuclear factor NF-kappa B acts as a lymphoid-specific and inducible enhancer element. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1482–1486. doi: 10.1073/pnas.85.5.1482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Poellinger L., Yoza B. K., Roeder R. G. Functional cooperativity between protein molecules bound at two distinct sequence elements of the immunoglobulin heavy-chain promoter. Nature. 1989 Feb 9;337(6207):573–576. doi: 10.1038/337573a0. [DOI] [PubMed] [Google Scholar]
  29. Queen C., Baltimore D. Immunoglobulin gene transcription is activated by downstream sequence elements. Cell. 1983 Jul;33(3):741–748. doi: 10.1016/0092-8674(83)90016-8. [DOI] [PubMed] [Google Scholar]
  30. Radbruch A., Burger C., Klein S., Müller W. Control of immunoglobulin class switch recombination. Immunol Rev. 1986 Feb;89:69–83. doi: 10.1111/j.1600-065x.1986.tb01473.x. [DOI] [PubMed] [Google Scholar]
  31. Schlissel M. S., Baltimore D. Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell. 1989 Sep 8;58(5):1001–1007. doi: 10.1016/0092-8674(89)90951-3. [DOI] [PubMed] [Google Scholar]
  32. Schreiber E., Matthias P., Müller M. M., Schaffner W. Identification of a novel lymphoid specific octamer binding protein (OTF-2B) by proteolytic clipping bandshift assay (PCBA). EMBO J. 1988 Dec 20;7(13):4221–4229. doi: 10.1002/j.1460-2075.1988.tb03319.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shimizu A., Takahashi N., Yamawaki-Kataoka Y., Nishida Y., Kataoka T., Honjo T. Ordering of mouse immunoglobulin heavy chain genes by molecular cloning. Nature. 1981 Jan 15;289(5794):149–153. doi: 10.1038/289149a0. [DOI] [PubMed] [Google Scholar]
  35. Staudt L. M., Singh H., Sen R., Wirth T., Sharp P. A., Baltimore D. A lymphoid-specific protein binding to the octamer motif of immunoglobulin genes. Nature. 1986 Oct 16;323(6089):640–643. doi: 10.1038/323640a0. [DOI] [PubMed] [Google Scholar]
  36. Stavnezer-Nordgren J., Sirlin S. Specificity of immunoglobulin heavy chain switch correlates with activity of germline heavy chain genes prior to switching. EMBO J. 1986 Jan;5(1):95–102. doi: 10.1002/j.1460-2075.1986.tb04182.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stavnezer J., Radcliffe G., Lin Y. C., Nietupski J., Berggren L., Sitia R., Severinson E. Immunoglobulin heavy-chain switching may be directed by prior induction of transcripts from constant-region genes. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7704–7708. doi: 10.1073/pnas.85.20.7704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sturm R. A., Das G., Herr W. The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain. Genes Dev. 1988 Dec;2(12A):1582–1599. doi: 10.1101/gad.2.12a.1582. [DOI] [PubMed] [Google Scholar]
  39. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. doi: 10.1038/302575a0. [DOI] [PubMed] [Google Scholar]
  40. Wabl M. R., Burrows P. D. Expression of immunoglobulin heavy chain at a high level in the absence of a proposed immunoglobulin enhancer element in cis. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2452–2455. doi: 10.1073/pnas.81.8.2452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Winoto A., Baltimore D. A novel, inducible and T cell-specific enhancer located at the 3' end of the T cell receptor alpha locus. EMBO J. 1989 Mar;8(3):729–733. doi: 10.1002/j.1460-2075.1989.tb03432.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Winter E., Krawinkel U., Radbruch A. Directed Ig class switch recombination in activated murine B cells. EMBO J. 1987 Jun;6(6):1663–1671. doi: 10.1002/j.1460-2075.1987.tb02415.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yancopoulos G. D., Alt F. W. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell. 1985 Feb;40(2):271–281. doi: 10.1016/0092-8674(85)90141-2. [DOI] [PubMed] [Google Scholar]

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