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. 1996 Sep 2;15(17):4665–4675.

Context dependent transactivation domains activate the immunoglobulin mu heavy chain gene enhancer.

B Erman 1, R Sen 1
PMCID: PMC452198  PMID: 8887557

Abstract

Enhancers and promoters nucleate the assembly of multiprotein complexes that are required for the transcriptional activation of eukaryotic genes. Although multimerized binding sites of individual transcription factors sometimes mimic the properties of an enhancer, the combinatorial use of factors is considered to be crucial for achieving biological specificity. The minimal B cell specific immunoglobulin mu heavy chain gene enhancer is activated by a combination of tissue-restricted ETS proteins and ubiquitously expressed basic helix-loop-helix transcription factors. Here we show that a domain of PU.1 that activates transcription from multimerized PU.1 binding sites is not required to activate the mu enhancer together with Ets-1. In contrast, a transactivation domain in Ets-1 is necessary to activate this enhancer synergistically with PU.1. Furthermore, the Ets-1 activation domain functions only when tethered to the muA site of the enhancer. These observations illuminate two forms of context dependence: first, all possible transcription activation domains may not be required to achieve combinatorial specificity; second, functional transcription activation domains may require appropriate positioning on DNA.

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Selected References

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

  1. Adams J. M., Harris A. W., Pinkert C. A., Corcoran L. M., Alexander W. S., Cory S., Palmiter R. D., Brinster R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. doi: 10.1038/318533a0. [DOI] [PubMed] [Google Scholar]
  2. Alt F. W., Blackwell T. K., DePinho R. A., Reth M. G., Yancopoulos G. D. Regulation of genome rearrangement events during lymphocyte differentiation. Immunol Rev. 1986 Feb;89:5–30. doi: 10.1111/j.1600-065x.1986.tb01470.x. [DOI] [PubMed] [Google Scholar]
  3. Artandi S. E., Cooper C., Shrivastava A., Calame K. The basic helix-loop-helix-zipper domain of TFE3 mediates enhancer-promoter interaction. Mol Cell Biol. 1994 Dec;14(12):7704–7716. doi: 10.1128/mcb.14.12.7704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beckmann H., Su L. K., Kadesch T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 1990 Feb;4(2):167–179. doi: 10.1101/gad.4.2.167. [DOI] [PubMed] [Google Scholar]
  5. Blackwell T. K., Huang J., Ma A., Kretzner L., Alt F. W., Eisenman R. N., Weintraub H. Binding of myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol. 1993 Sep;13(9):5216–5224. doi: 10.1128/mcb.13.9.5216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carlsson P., Waterman M. L., Jones K. A. The hLEF/TCF-1 alpha HMG protein contains a context-dependent transcriptional activation domain that induces the TCR alpha enhancer in T cells. Genes Dev. 1993 Dec;7(12A):2418–2430. doi: 10.1101/gad.7.12a.2418. [DOI] [PubMed] [Google Scholar]
  7. Chen J., Young F., Bottaro A., Stewart V., Smith R. K., Alt F. W. Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus. EMBO J. 1993 Dec;12(12):4635–4645. doi: 10.1002/j.1460-2075.1993.tb06152.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dalton S., Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. doi: 10.1016/0092-8674(92)90194-h. [DOI] [PubMed] [Google Scholar]
  9. Davis R. L., Weintraub H. Acquisition of myogenic specificity by replacement of three amino acid residues from MyoD into E12. Science. 1992 May 15;256(5059):1027–1030. doi: 10.1126/science.1317057. [DOI] [PubMed] [Google Scholar]
  10. Donaldson L. W., Petersen J. M., Graves B. J., McIntosh L. P. Secondary structure of the ETS domain places murine Ets-1 in the superfamily of winged helix-turn-helix DNA-binding proteins. Biochemistry. 1994 Nov 22;33(46):13509–13516. doi: 10.1021/bi00250a001. [DOI] [PubMed] [Google Scholar]
  11. Gegonne A., Punyammalee B., Rabault B., Bosselut R., Seneca S., Crabeel M., Ghysdael J. Analysis of the DNA binding and transcriptional activation properties of the Ets1 oncoprotein. New Biol. 1992 May;4(5):512–519. [PubMed] [Google Scholar]
  12. Giese K., Grosschedl R. LEF-1 contains an activation domain that stimulates transcription only in a specific context of factor-binding sites. EMBO J. 1993 Dec;12(12):4667–4676. doi: 10.1002/j.1460-2075.1993.tb06155.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Giese K., Kingsley C., Kirshner J. R., Grosschedl R. Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev. 1995 Apr 15;9(8):995–1008. doi: 10.1101/gad.9.8.995. [DOI] [PubMed] [Google Scholar]
  14. Gregor P. D., Sawadogo M., Roeder R. G. The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 1990 Oct;4(10):1730–1740. doi: 10.1101/gad.4.10.1730. [DOI] [PubMed] [Google Scholar]
  15. Gunther C. V., Nye J. A., Bryner R. S., Graves B. J. Sequence-specific DNA binding of the proto-oncoprotein ets-1 defines a transcriptional activator sequence within the long terminal repeat of the Moloney murine sarcoma virus. Genes Dev. 1990 Apr;4(4):667–679. doi: 10.1101/gad.4.4.667. [DOI] [PubMed] [Google Scholar]
  16. Hagemeier C., Bannister A. J., Cook A., Kouzarides T. The activation domain of transcription factor PU.1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1580–1584. doi: 10.1073/pnas.90.4.1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hagman J., Grosschedl R. An inhibitory carboxyl-terminal domain in Ets-1 and Ets-2 mediates differential binding of ETS family factors to promoter sequences of the mb-1 gene. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8889–8893. doi: 10.1073/pnas.89.19.8889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hagman J., Gutch M. J., Lin H., Grosschedl R. EBF contains a novel zinc coordination motif and multiple dimerization and transcriptional activation domains. EMBO J. 1995 Jun 15;14(12):2907–2916. doi: 10.1002/j.1460-2075.1995.tb07290.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hipskind R. A., Rao V. N., Mueller C. G., Reddy E. S., Nordheim A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature. 1991 Dec 19;354(6354):531–534. doi: 10.1038/354531a0. [DOI] [PubMed] [Google Scholar]
  20. Ho I. C., Bhat N. K., Gottschalk L. R., Lindsten T., Thompson C. B., Papas T. S., Leiden J. M. Sequence-specific binding of human Ets-1 to the T cell receptor alpha gene enhancer. Science. 1990 Nov 9;250(4982):814–818. doi: 10.1126/science.2237431. [DOI] [PubMed] [Google Scholar]
  21. Hollenberg S. M., Evans R. M. Multiple and cooperative trans-activation domains of the human glucocorticoid receptor. Cell. 1988 Dec 2;55(5):899–906. doi: 10.1016/0092-8674(88)90145-6. [DOI] [PubMed] [Google Scholar]
  22. Kadesch T. Helix-loop-helix proteins in the regulation of immunoglobulin gene transcription. Immunol Today. 1992 Jan;13(1):31–36. doi: 10.1016/0167-5699(92)90201-h. [DOI] [PubMed] [Google Scholar]
  23. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  24. Kominato Y., Galson D., Waterman W. R., Webb A. C., Auron P. E. Monocyte expression of the human prointerleukin 1 beta gene (IL1B) is dependent on promoter sequences which bind the hematopoietic transcription factor Spi-1/PU.1. Mol Cell Biol. 1995 Jan;15(1):58–68. [PMC free article] [PubMed] [Google Scholar]
  25. Langdon W. Y., Harris A. W., Cory S., Adams J. M. The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell. 1986 Oct 10;47(1):11–18. doi: 10.1016/0092-8674(86)90361-2. [DOI] [PubMed] [Google Scholar]
  26. Liang H., Olejniczak E. T., Mao X., Nettesheim D. G., Yu L., Thompson C. B., Fesik S. W. The secondary structure of the ets domain of human Fli-1 resembles that of the helix-turn-helix DNA-binding motif of the Escherichia coli catabolite gene activator protein. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11655–11659. doi: 10.1073/pnas.91.24.11655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Libermann T. A., Baltimore D. Pi, a pre-B-cell-specific enhancer element in the immunoglobulin heavy-chain enhancer. Mol Cell Biol. 1993 Oct;13(10):5957–5969. doi: 10.1128/mcb.13.10.5957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lim F., Kraut N., Framptom J., Graf T. DNA binding by c-Ets-1, but not v-Ets, is repressed by an intramolecular mechanism. EMBO J. 1992 Feb;11(2):643–652. doi: 10.1002/j.1460-2075.1992.tb05096.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nelsen B., Kadesch T., Sen R. Complex regulation of the immunoglobulin mu heavy-chain gene enhancer: microB, a new determinant of enhancer function. Mol Cell Biol. 1990 Jun;10(6):3145–3154. doi: 10.1128/mcb.10.6.3145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nelsen B., Sen R. Regulation of immunoglobulin gene transcription. Int Rev Cytol. 1992;133:121–149. doi: 10.1016/s0074-7696(08)61859-8. [DOI] [PubMed] [Google Scholar]
  31. Nelsen B., Tian G., Erman B., Gregoire J., Maki R., Graves B., Sen R. Regulation of lymphoid-specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins. Science. 1993 Jul 2;261(5117):82–86. doi: 10.1126/science.8316859. [DOI] [PubMed] [Google Scholar]
  32. Nye J. A., Petersen J. M., Gunther C. V., Jonsen M. D., Graves B. J. Interaction of murine ets-1 with GGA-binding sites establishes the ETS domain as a new DNA-binding motif. Genes Dev. 1992 Jun;6(6):975–990. doi: 10.1101/gad.6.6.975. [DOI] [PubMed] [Google Scholar]
  33. Oltz E. M., Alt F. W., Lin W. C., Chen J., Taccioli G., Desiderio S., Rathbun G. A V(D)J recombinase-inducible B-cell line: role of transcriptional enhancer elements in directing V(D)J recombination. Mol Cell Biol. 1993 Oct;13(10):6223–6230. doi: 10.1128/mcb.13.10.6223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pomerantz J. L., Kristie T. M., Sharp P. A. Recognition of the surface of a homeo domain protein. Genes Dev. 1992 Nov;6(11):2047–2057. doi: 10.1101/gad.6.11.2047. [DOI] [PubMed] [Google Scholar]
  35. Pongubala J. M., Nagulapalli S., Klemsz M. J., McKercher S. R., Maki R. A., Atchison M. L. PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3' enhancer activity. Mol Cell Biol. 1992 Jan;12(1):368–378. doi: 10.1128/mcb.12.1.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pongubala J. M., Van Beveren C., Nagulapalli S., Klemsz M. J., McKercher S. R., Maki R. A., Atchison M. L. Effect of PU.1 phosphorylation on interaction with NF-EM5 and transcriptional activation. Science. 1993 Mar 12;259(5101):1622–1625. doi: 10.1126/science.8456286. [DOI] [PubMed] [Google Scholar]
  37. Reik W., Williams G., Barton S., Norris M., Neuberger M., Surani M. A. Provision of the immunoglobulin heavy chain enhancer downstream of a test gene is sufficient to confer lymphoid-specific expression in transgenic mice. Eur J Immunol. 1987 Apr;17(4):465–469. doi: 10.1002/eji.1830170405. [DOI] [PubMed] [Google Scholar]
  38. Rivera R. R., Stuiver M. H., Steenbergen R., Murre C. Ets proteins: new factors that regulate immunoglobulin heavy-chain gene expression. Mol Cell Biol. 1993 Nov;13(11):7163–7169. doi: 10.1128/mcb.13.11.7163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Roman C., Matera A. G., Cooper C., Artandi S., Blain S., Ward D. C., Calame K. mTFE3, an X-linked transcriptional activator containing basic helix-loop-helix and zipper domains, utilizes the zipper to stabilize both DNA binding and multimerization. Mol Cell Biol. 1992 Feb;12(2):817–827. doi: 10.1128/mcb.12.2.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schmidt E. V., Pattengale P. K., Weir L., Leder P. Transgenic mice bearing the human c-myc gene activated by an immunoglobulin enhancer: a pre-B-cell lymphoma model. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6047–6051. doi: 10.1073/pnas.85.16.6047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Schneikert J., Lutz Y., Wasylyk B. Two independent activation domains in c-Ets-1 and c-Ets-2 located in non-conserved sequences of the ets gene family. Oncogene. 1992 Feb;7(2):249–256. [PubMed] [Google Scholar]
  42. Serwe M., Sablitzky F. V(D)J recombination in B cells is impaired but not blocked by targeted deletion of the immunoglobulin heavy chain intron enhancer. EMBO J. 1993 Jun;12(6):2321–2327. doi: 10.1002/j.1460-2075.1993.tb05886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Shin M. K., Koshland M. E. Ets-related protein PU.1 regulates expression of the immunoglobulin J-chain gene through a novel Ets-binding element. Genes Dev. 1993 Oct;7(10):2006–2015. doi: 10.1101/gad.7.10.2006. [DOI] [PubMed] [Google Scholar]
  44. Thompson C. C., Brown T. A., McKnight S. L. Convergence of Ets- and notch-related structural motifs in a heteromeric DNA binding complex. Science. 1991 Aug 16;253(5021):762–768. doi: 10.1126/science.1876833. [DOI] [PubMed] [Google Scholar]
  45. Wasylyk B., Hahn S. L., Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. doi: 10.1007/978-3-642-78757-7_2. [DOI] [PubMed] [Google Scholar]
  46. Wasylyk C., Kerckaert J. P., Wasylyk B. A novel modulator domain of Ets transcription factors. Genes Dev. 1992 Jun;6(6):965–974. doi: 10.1101/gad.6.6.965. [DOI] [PubMed] [Google Scholar]
  47. Watson D. K., McWilliams M. J., Lapis P., Lautenberger J. A., Schweinfest C. W., Papas T. S. Mammalian ets-1 and ets-2 genes encode highly conserved proteins. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7862–7866. doi: 10.1073/pnas.85.21.7862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Wotton D., Ghysdael J., Wang S., Speck N. A., Owen M. J. Cooperative binding of Ets-1 and core binding factor to DNA. Mol Cell Biol. 1994 Jan;14(1):840–850. doi: 10.1128/mcb.14.1.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. 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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