Skip to main content
PMC home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1994 Oct 11;22(20):4202–4210. doi: 10.1093/nar/22.20.4202

Dissection of the locus control function located on the chicken lysozyme gene domain in transgenic mice.

C Bonifer 1, N Yannoutsos 1, G Krüger 1, F Grosveld 1, A E Sippel 1
PMCID: PMC331921  PMID: 7937146

Abstract

The entire chicken lysozyme gene locus including all known cis-regulatory sequences and the 5' and 3' matrix attachment sites defining the borders of the DNase I sensitive chromatin domain, is expressed at a high level and independent of its chromosomal position in macrophages of transgenic mice. It was concluded that the lysozyme gene locus carries a locus control function. We analysed several cis-regulatory deletion mutants to investigate their influence on tissue specificity and level of expression. Position independent expression of the gene is lost whenever one of the upstream tissue specific enhancer regions is deleted, although tissue specific expression is usually retained. Deletion of the domain border fragments has no influence on copy number dependency of expression. However, without these regions an increased incidence of ectopic expression is observed. This suggests that the domain border fragments may help to suppress transgene expression in inappropriate tissues. We conclude, that position independent expression of the lysozyme gene is not controlled by a single specific region of the locus but is the result of the concerted action of several tissue specific upstream regulatory DNA elements with the promoter.

Full text

PDF
4202

Images in this article

4206Image
on p.4206
4206Image
on p.4206
4207Image
on p.4207
4208Image
on p.4208

Selected References

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

  1. Alevy M. C., Tsai M. J., O'Malley B. W. DNase I sensitive domain of the gene coding for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase. Biochemistry. 1984 May 8;23(10):2309–2314. doi: 10.1021/bi00305a034. [DOI] [PubMed] [Google Scholar]
  2. Altschmied J., Muller M., Baniahmad A., Steiner C., Renkawitz R. Cooperative interaction of chicken lysozyme enhancer sub-domains partially overlapping with a steroid receptor binding site. Nucleic Acids Res. 1989 Jul 11;17(13):4975–4991. doi: 10.1093/nar/17.13.4975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aronow B. J., Silbiger R. N., Dusing M. R., Stock J. L., Yager K. L., Potter S. S., Hutton J. J., Wiginton D. A. Functional analysis of the human adenosine deaminase gene thymic regulatory region and its ability to generate position-independent transgene expression. Mol Cell Biol. 1992 Sep;12(9):4170–4185. doi: 10.1128/mcb.12.9.4170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  5. Baniahmad A., Muller M., Steiner C., Renkawitz R. Activity of two different silencer elements of the chicken lysozyme gene can be compensated by enhancer elements. EMBO J. 1987 Aug;6(8):2297–2303. doi: 10.1002/j.1460-2075.1987.tb02504.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beug H., von Kirchbach A., Döderlein G., Conscience J. F., Graf T. Chicken hematopoietic cells transformed by seven strains of defective avian leukemia viruses display three distinct phenotypes of differentiation. Cell. 1979 Oct;18(2):375–390. doi: 10.1016/0092-8674(79)90057-6. [DOI] [PubMed] [Google Scholar]
  7. Blom van Assendelft G., Hanscombe O., Grosveld F., Greaves D. R. The beta-globin dominant control region activates homologous and heterologous promoters in a tissue-specific manner. Cell. 1989 Mar 24;56(6):969–977. doi: 10.1016/0092-8674(89)90630-2. [DOI] [PubMed] [Google Scholar]
  8. Bonifer C., Hecht A., Saueressig H., Winter D. M., Sippel A. E. Dynamic chromatin: the regulatory domain organization of eukaryotic gene loci. J Cell Biochem. 1991 Oct;47(2):99–108. doi: 10.1002/jcb.240470203. [DOI] [PubMed] [Google Scholar]
  9. Bonifer C., Vidal M., Grosveld F., Sippel A. E. Tissue specific and position independent expression of the complete gene domain for chicken lysozyme in transgenic mice. EMBO J. 1990 Sep;9(9):2843–2848. doi: 10.1002/j.1460-2075.1990.tb07473.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brinster R. L., Chen H. Y., Trumbauer M. E., Yagle M. K., Palmiter R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. doi: 10.1073/pnas.82.13.4438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Carson S., Wiles M. V. Far upstream regions of class II MHC Ea are necessary for position-independent, copy-dependent expression of Ea transgene. Nucleic Acids Res. 1993 May 11;21(9):2065–2072. doi: 10.1093/nar/21.9.2065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chamberlain J. W., Vasavada H. A., Ganguly S., Weissman S. M. Identification of cis sequences controlling efficient position-independent tissue-specific expression of human major histocompatibility complex class I genes in transgenic mice. Mol Cell Biol. 1991 Jul;11(7):3564–3572. doi: 10.1128/mcb.11.7.3564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  14. Chung L. P., Keshav S., Gordon S. Cloning the human lysozyme cDNA: inverted Alu repeat in the mRNA and in situ hybridization for macrophages and Paneth cells. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6227–6231. doi: 10.1073/pnas.85.17.6227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cross M., Mangelsdorf I., Wedel A., Renkawitz R. Mouse lysozyme M gene: isolation, characterization, and expression studies. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6232–6236. doi: 10.1073/pnas.85.17.6232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ellis J., Talbot D., Dillon N., Grosveld F. Synthetic human beta-globin 5'HS2 constructs function as locus control regions only in multicopy transgene concatamers. EMBO J. 1993 Jan;12(1):127–134. doi: 10.1002/j.1460-2075.1993.tb05638.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Forrester W. C., Epner E., Driscoll M. C., Enver T., Brice M., Papayannopoulou T., Groudine M. A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus. Genes Dev. 1990 Oct;4(10):1637–1649. doi: 10.1101/gad.4.10.1637. [DOI] [PubMed] [Google Scholar]
  18. Forrester W. C., Takegawa S., Papayannopoulou T., Stamatoyannopoulos G., Groudine M. Evidence for a locus activation region: the formation of developmentally stable hypersensitive sites in globin-expressing hybrids. Nucleic Acids Res. 1987 Dec 23;15(24):10159–10177. doi: 10.1093/nar/15.24.10159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Forrester W. C., Thompson C., Elder J. T., Groudine M. A developmentally stable chromatin structure in the human beta-globin gene cluster. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1359–1363. doi: 10.1073/pnas.83.5.1359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fraser P., Pruzina S., Antoniou M., Grosveld F. Each hypersensitive site of the human beta-globin locus control region confers a different developmental pattern of expression on the globin genes. Genes Dev. 1993 Jan;7(1):106–113. doi: 10.1101/gad.7.1.106. [DOI] [PubMed] [Google Scholar]
  21. Fritton H. P., Igo-Kemenes T., Nowock J., Strech-Jurk U., Theisen M., Sippel A. E. Alternative sets of DNase I-hypersensitive sites characterize the various functional states of the chicken lysozyme gene. Nature. 1984 Sep 13;311(5982):163–165. doi: 10.1038/311163a0. [DOI] [PubMed] [Google Scholar]
  22. Fritton H. P., Igo-Kemenes T., Nowock J., Strech-Jurk U., Theisen M., Sippel A. E. DNase I-hypersensitive sites in the chromatin structure of the lysozyme gene in steroid hormone target and non-target cells. Biol Chem Hoppe Seyler. 1987 Feb;368(2):111–119. doi: 10.1515/bchm3.1987.368.1.111. [DOI] [PubMed] [Google Scholar]
  23. Fritton H. P., Sippel A. E., Igo-Kemenes T. Nuclease-hypersensitive sites in the chromatin domain of the chicken lysozyme gene. Nucleic Acids Res. 1983 Jun 11;11(11):3467–3485. doi: 10.1093/nar/11.11.3467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Greaves D. R., Wilson F. D., Lang G., Kioussis D. Human CD2 3'-flanking sequences confer high-level, T cell-specific, position-independent gene expression in transgenic mice. Cell. 1989 Mar 24;56(6):979–986. doi: 10.1016/0092-8674(89)90631-4. [DOI] [PubMed] [Google Scholar]
  25. Grewal T., Theisen M., Borgmeyer U., Grussenmeyer T., Rupp R. A., Stief A., Qian F., Hecht A., Sippel A. E. The -6.1-kilobase chicken lysozyme enhancer is a multifactorial complex containing several cell-type-specific elements. Mol Cell Biol. 1992 May;12(5):2339–2350. doi: 10.1128/mcb.12.5.2339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Grez M., Land H., Giesecke K., Schütz G., Jung A., Sippel A. E. Multiple mRNAs are generated from the chicken lysozyme gene. Cell. 1981 Sep;25(3):743–752. doi: 10.1016/0092-8674(81)90182-3. [DOI] [PubMed] [Google Scholar]
  27. Gross D. S., Garrard W. T. Nuclease hypersensitive sites in chromatin. Annu Rev Biochem. 1988;57:159–197. doi: 10.1146/annurev.bi.57.070188.001111. [DOI] [PubMed] [Google Scholar]
  28. Grosveld F., van Assendelft G. B., Greaves D. R., Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987 Dec 24;51(6):975–985. doi: 10.1016/0092-8674(87)90584-8. [DOI] [PubMed] [Google Scholar]
  29. Gunning P., Ponte P., Okayama H., Engel J., Blau H., Kedes L. Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol Cell Biol. 1983 May;3(5):787–795. doi: 10.1128/mcb.3.5.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hecht A., Berkenstam A., Strömstedt P. E., Gustafsson J. A., Sippel A. E. A progesterone responsive element maps to the far upstream steroid dependent DNase hypersensitive site of chicken lysozyme chromatin. EMBO J. 1988 Jul;7(7):2063–2073. doi: 10.1002/j.1460-2075.1988.tb03046.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Higgs D. R., Wood W. G., Jarman A. P., Sharpe J., Lida J., Pretorius I. M., Ayyub H. A major positive regulatory region located far upstream of the human alpha-globin gene locus. Genes Dev. 1990 Sep;4(9):1588–1601. doi: 10.1101/gad.4.9.1588. [DOI] [PubMed] [Google Scholar]
  32. Jantzen K., Fritton H. P., Igo-Kemenes T. The DNase I sensitive domain of the chicken lysozyme gene spans 24 kb. Nucleic Acids Res. 1986 Aug 11;14(15):6085–6099. doi: 10.1093/nar/14.15.6085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Jiménez G., Griffiths S. D., Ford A. M., Greaves M. F., Enver T. Activation of the beta-globin locus control region precedes commitment to the erythroid lineage. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10618–10622. doi: 10.1073/pnas.89.22.10618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kollias G., Wrighton N., Hurst J., Grosveld F. Regulated expression of human A gamma-, beta-, and hybrid gamma beta-globin genes in transgenic mice: manipulation of the developmental expression patterns. Cell. 1986 Jul 4;46(1):89–94. doi: 10.1016/0092-8674(86)90862-7. [DOI] [PubMed] [Google Scholar]
  35. Latham K. E., Solter D., Schultz R. M. Acquisition of a transcriptionally permissive state during the 1-cell stage of mouse embryogenesis. Dev Biol. 1992 Feb;149(2):457–462. doi: 10.1016/0012-1606(92)90300-6. [DOI] [PubMed] [Google Scholar]
  36. Lawson G. M., Tsai M. J., O'Malley B. W. Deoxyribonuclease I sensitivity of the nontranscribed sequences flanking the 5' and 3' ends of the ovomucoid gene and the ovalbumin and its related X and Y genes in hen oviduct nuclei. Biochemistry. 1980 Sep 16;19(19):4403–4441. doi: 10.1021/bi00560a004. [DOI] [PubMed] [Google Scholar]
  37. Lee M. S., Garrard W. T. Transcription-induced nucleosome 'splitting': an underlying structure for DNase I sensitive chromatin. EMBO J. 1991 Mar;10(3):607–615. doi: 10.1002/j.1460-2075.1991.tb07988.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lindenmaier W., Nguyen-Huu M. C., Lurz R., Stratmann M., Blin N., Wurtz T., Hauser H. J., Sippel A. E., Schütz G. Arrangement of coding and intervening sequences of chicken lysozyme gene. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6196–6200. doi: 10.1073/pnas.76.12.6196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Loc P. V., Strätling W. H. The matrix attachment regions of the chicken lysozyme gene co-map with the boundaries of the chromatin domain. EMBO J. 1988 Mar;7(3):655–664. doi: 10.1002/j.1460-2075.1988.tb02860.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Müller A., Grussenmeyer T., Strech-Jurk U., Theisen M., Stief A., Sippel A. E. Macrophage differentiation at the genome level: studies of lysozyme gene activation. Bone Marrow Transplant. 1990 Jan;5 (Suppl 1):13–14. [PubMed] [Google Scholar]
  41. Neznanov N., Thorey I. S., Ceceña G., Oshima R. G. Transcriptional insulation of the human keratin 18 gene in transgenic mice. Mol Cell Biol. 1993 Apr;13(4):2214–2223. doi: 10.1128/mcb.13.4.2214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Palmiter R. D., Sandgren E. P., Koeller D. M., Brinster R. L. Distal regulatory elements from the mouse metallothionein locus stimulate gene expression in transgenic mice. Mol Cell Biol. 1993 Sep;13(9):5266–5275. doi: 10.1128/mcb.13.9.5266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Phi-Van L., von Kries J. P., Ostertag W., Strätling W. H. The chicken lysozyme 5' matrix attachment region increases transcription from a heterologous promoter in heterologous cells and dampens position effects on the expression of transfected genes. Mol Cell Biol. 1990 May;10(5):2302–2307. doi: 10.1128/mcb.10.5.2302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reitman M., Lee E., Westphal H., Felsenfeld G. An enhancer/locus control region is not sufficient to open chromatin. Mol Cell Biol. 1993 Jul;13(7):3990–3998. doi: 10.1128/mcb.13.7.3990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Reitman M., Lee E., Westphal H., Felsenfeld G. Site-independent expression of the chicken beta A-globin gene in transgenic mice. Nature. 1990 Dec 20;348(6303):749–752. doi: 10.1038/348749a0. [DOI] [PubMed] [Google Scholar]
  46. Schedl A., Montoliu L., Kelsey G., Schütz G. A yeast artificial chromosome covering the tyrosinase gene confers copy number-dependent expression in transgenic mice. Nature. 1993 Mar 18;362(6417):258–261. doi: 10.1038/362258a0. [DOI] [PubMed] [Google Scholar]
  47. Steiner C., Muller M., Baniahmad A., Renkawitz R. Lysozyme gene activity in chicken macrophages is controlled by positive and negative regulatory elements. Nucleic Acids Res. 1987 May 26;15(10):4163–4178. doi: 10.1093/nar/15.10.4163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Stief A., Winter D. M., Strätling W. H., Sippel A. E. A nuclear DNA attachment element mediates elevated and position-independent gene activity. Nature. 1989 Sep 28;341(6240):343–345. doi: 10.1038/341343a0. [DOI] [PubMed] [Google Scholar]
  49. Strauss W. M., Dausman J., Beard C., Johnson C., Lawrence J. B., Jaenisch R. Germ line transmission of a yeast artificial chromosome spanning the murine alpha 1(I) collagen locus. Science. 1993 Mar 26;259(5103):1904–1907. doi: 10.1126/science.8096090. [DOI] [PubMed] [Google Scholar]
  50. Theisen M., Stief A., Sippel A. E. The lysozyme enhancer: cell-specific activation of the chicken lysozyme gene by a far-upstream DNA element. EMBO J. 1986 Apr;5(4):719–724. doi: 10.1002/j.1460-2075.1986.tb04273.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES