Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1983 Aug;80(15):4689–4693. doi: 10.1073/pnas.80.15.4689

Methylation status and DNase I sensitivity of immunoglobulin genes: changes associated with rearrangement.

E L Mather, R P Perry
PMCID: PMC384109  PMID: 6308642

Abstract

Immunoglobulin V kappa genes are transcriptionally silent in their germline context and become transcriptionally active upon fusion to the J kappa-C kappa region (kappa locus). To elucidate the role of chromosomal structure in this regulatory phenomenon we have investigated the DNase I sensitivity and methylation status of the kappa locus and selected V kappa genes in a variety of alleles exhibiting different rearrangement configurations and different levels of transcriptional activity. Our findings indicate that the kappa locus in either germline or rearranged contexts maintains a distinctive DNase I-sensitive, hypomethylated structure in plasmacytomas and hybridomas, irrespective of its level of transcriptional activity. In contrast, the germline V kappa genes are in less accessible regions of chromatin and more highly methylated regions of DNA. Upon fusion to the kappa locus, V kappa genes become DNase I-sensitive and hypomethylated. This effect extends several kilobases upstream of the transcriptional initiation site but does not extend to the adjacent V kappa gene or to the identical V kappa allele on the other chromosome, indicating that the structural alteration is a localized cis-acting phenomenon.

Full text

PDF
4689

Images in this article

4690Image
on p.4690
4690Image
on p.4690
4690Image
on p.4690
4690Image
on p.4690
4690Image
on p.4690
4691Image
on p.4691
4692Image
on p.4692

Selected References

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

  1. Alt F. W., Rosenberg N., Enea V., Siden E., Baltimore D. Multiple immunoglobulin heavy-chain gene transcripts in Abelson murine leukemia virus-transformed lymphoid cell lines. Mol Cell Biol. 1982 Apr;2(4):386–400. doi: 10.1128/mcb.2.4.386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Choi E., Kuehl M., Wall R. RNA splicing generates a variant light chain from an aberrantly rearranged kappa gene. Nature. 1980 Aug 21;286(5775):776–779. doi: 10.1038/286776a0. [DOI] [PubMed] [Google Scholar]
  3. Chung S. Y., Folsom V., Wooley J. DNase I-hypersensitive sites in the chromatin of immunoglobulin kappa light chain genes. Proc Natl Acad Sci U S A. 1983 May;80(9):2427–2431. doi: 10.1073/pnas.80.9.2427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Coleclough C., Cooper D., Perry R. P. Rearrangement of immunoglobulin heavy chain genes during B-lymphocyte development as revealed by studies of mouse plasmacytoma cells. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1422–1426. doi: 10.1073/pnas.77.3.1422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coleclough C., Perry R. P., Karjalainen K., Weigert M. Aberrant rearrangements contribute significantly to the allelic exclusion of immunoglobulin gene expression. Nature. 1981 Apr 2;290(5805):372–378. doi: 10.1038/290372a0. [DOI] [PubMed] [Google Scholar]
  6. Compere S. J., Palmiter R. D. DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Cell. 1981 Jul;25(1):233–240. doi: 10.1016/0092-8674(81)90248-8. [DOI] [PubMed] [Google Scholar]
  7. Fradin A., Manley J. L., Prives C. L. Methylation of simian virus 40 Hpa II site affects late, but not early, viral gene expression. Proc Natl Acad Sci U S A. 1982 Sep;79(17):5142–5146. doi: 10.1073/pnas.79.17.5142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gorin M. B., Tilghman S. M. Structure of the alpha-fetoprotein gene in the mouse. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1351–1355. doi: 10.1073/pnas.77.3.1351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Grosschedl R., Birnstiel M. L. Spacer DNA sequences upstream of the T-A-T-A-A-A-T-A sequence are essential for promotion of H2A histone gene transcription in vivo. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7102–7106. doi: 10.1073/pnas.77.12.7102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Groudine M., Eisenman R., Weintraub H. Chromatin structure of endogenous retroviral genes and activation by an inhibitor of DNA methylation. Nature. 1981 Jul 23;292(5821):311–317. doi: 10.1038/292311a0. [DOI] [PubMed] [Google Scholar]
  11. Gruss P., Dhar R., Khoury G. Simian virus 40 tandem repeated sequences as an element of the early promoter. Proc Natl Acad Sci U S A. 1981 Feb;78(2):943–947. doi: 10.1073/pnas.78.2.943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kelley D. E., Coleclough C., Perry R. P. Functional significance and evolutionary development of the 5'-terminal regions of immunoglobulin variable-region genes. Cell. 1982 Jun;29(2):681–689. doi: 10.1016/0092-8674(82)90184-2. [DOI] [PubMed] [Google Scholar]
  13. Kemp D. J., Harris A. W., Cory S., Adams J. M. Expression of the immunoglobulin C mu gene in mouse T and B lymphoid and myeloid cell lines. Proc Natl Acad Sci U S A. 1980 May;77(5):2876–2880. doi: 10.1073/pnas.77.5.2876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mather E. L., Perry R. P. Transcriptional regulation of immunoglobulin V genes. Nucleic Acids Res. 1981 Dec 21;9(24):6855–6867. doi: 10.1093/nar/9.24.6855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Max E. E., Maizel J. V., Jr, Leder P. The nucleotide sequence of a 5.5-kilobase DNA segment containing the mouse kappa immunoglobulin J and C region genes. J Biol Chem. 1981 May 25;256(10):5116–5120. [PubMed] [Google Scholar]
  16. Max E. E., Seidman J. G., Leder P. Sequences of five potential recombination sites encoded close to an immunoglobulin kappa constant region gene. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3450–3454. doi: 10.1073/pnas.76.7.3450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. McKnight S. L., Kingsbury R. Transcriptional control signals of a eukaryotic protein-coding gene. Science. 1982 Jul 23;217(4557):316–324. doi: 10.1126/science.6283634. [DOI] [PubMed] [Google Scholar]
  18. Parslow T. G., Granner D. K. Chromatin changes accompany immunoglobulin kappa gene activation: a potential control region within the gene. Nature. 1982 Sep 30;299(5882):449–451. doi: 10.1038/299449a0. [DOI] [PubMed] [Google Scholar]
  19. Perry R. P., Coleclough C., Weigert M. Reorganization and expression of immunoglobulin genes: status of allelic elements. Cold Spring Harb Symp Quant Biol. 1981;45(Pt 2):925–933. doi: 10.1101/sqb.1981.045.01.109. [DOI] [PubMed] [Google Scholar]
  20. Perry R. P., Kelley D. E., Coleclough C., Kearney J. F. Organization and expression of immunoglobulin genes in fetal liver hybridomas. Proc Natl Acad Sci U S A. 1981 Jan;78(1):247–251. doi: 10.1073/pnas.78.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Perry R. P., Kelley D. E., Coleclough C., Seidman J. G., Leder P., Tonegawa S., Matthyssens G., Weigert M. Transcription of mouse kappa chain genes: implications for allelic exclusion. Proc Natl Acad Sci U S A. 1980 Apr;77(4):1937–1941. doi: 10.1073/pnas.77.4.1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Razin A., Riggs A. D. DNA methylation and gene function. Science. 1980 Nov 7;210(4470):604–610. doi: 10.1126/science.6254144. [DOI] [PubMed] [Google Scholar]
  23. Rogers J., Wall R. Immunoglobulin heavy chain genes: demethylation accompanies class switching. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7497–7501. doi: 10.1073/pnas.78.12.7497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sakano H., Hüppi K., Heinrich G., Tonegawa S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature. 1979 Jul 26;280(5720):288–294. doi: 10.1038/280288a0. [DOI] [PubMed] [Google Scholar]
  25. Schibler U., Marcu K. B., Perry R. P. The synthesis and processing of the messenger RNAs specifying heavy and light chain immunoglobulins in MPC-11 cells. Cell. 1978 Dec;15(4):1495–1509. doi: 10.1016/0092-8674(78)90072-7. [DOI] [PubMed] [Google Scholar]
  26. Seidman J. G., Leder P. A mutant immunoglobulin light chain is formed by aberrant DNA- and RNA-splicing events. Nature. 1980 Aug 21;286(5775):779–783. doi: 10.1038/286779a0. [DOI] [PubMed] [Google Scholar]
  27. Seidman J. G., Nau M. M., Norman B., Kwan S. P., Scharff M., Leder P. Immunoglobulin V/J recombination is accompanied by deletion of joining site and variable region segments. Proc Natl Acad Sci U S A. 1980 Oct;77(10):6022–6026. doi: 10.1073/pnas.77.10.6022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Storb U., Wilson R., Selsing E., Walfield A. Rearranged and germline immunoglobulin kappa genes: different states of DNase I sensitivity of constant kappa genes in immunocompetent and nonimmune cells. Biochemistry. 1981 Feb 17;20(4):990–996. doi: 10.1021/bi00507a053. [DOI] [PubMed] [Google Scholar]
  29. Van Ness B. G., Weigert M., Coleclough C., Mather E. L., Kelley D. E., Perry R. P. Transcription of the unrearranged mouse C kappa locus: sequence of the initiation region and comparison of activity with a rearranged V kappa-C kappa gene. Cell. 1981 Dec;27(3 Pt 2):593–602. doi: 10.1016/0092-8674(81)90401-3. [DOI] [PubMed] [Google Scholar]
  30. VanNess B. G., Shapiro M., Kelley D. E., Perry R. P., Weigert M., D'Eustachio P., Ruddle F. Aberrant rearrangement of the kappa light-chain locus involving the heavy-chain locus and chromosome 15 in a mouse plasmacytoma. Nature. 1983 Feb 3;301(5899):425–427. doi: 10.1038/301425a0. [DOI] [PubMed] [Google Scholar]
  31. Vardimon L., Kressmann A., Cedar H., Maechler M., Doerfler W. Expression of a cloned adenovirus gene is inhibited by in vitro methylation. Proc Natl Acad Sci U S A. 1982 Feb;79(4):1073–1077. doi: 10.1073/pnas.79.4.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weintraub H., Groudine M. Chromosomal subunits in active genes have an altered conformation. Science. 1976 Sep 3;193(4256):848–856. doi: 10.1126/science.948749. [DOI] [PubMed] [Google Scholar]
  33. Weisbrod S., Groudine M., Weintraub H. Interaction of HMG 14 and 17 with actively transcribed genes. Cell. 1980 Jan;19(1):289–301. doi: 10.1016/0092-8674(80)90410-9. [DOI] [PubMed] [Google Scholar]
  34. Weischet W. O., Glotov B. O., Schnell H., Zachau H. G. Differences in the nuclease sensitivity between the two alleles of the immunoglobulin kappa light chain genes in mouse liver and myeloma nuclei. Nucleic Acids Res. 1982 Jun 25;10(12):3627–3645. doi: 10.1093/nar/10.12.3627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yagi M., Koshland M. E. Expression of the J chain gene during B cell differentiation is inversely correlated with DNA methylation. Proc Natl Acad Sci U S A. 1981 Aug;78(8):4907–4911. doi: 10.1073/pnas.78.8.4907. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES