Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal-context- dependent manner

Nature Genetics volume 23, pages 457–461 (1999)Cite this article

Abstract

Locus control regions (LCRs) are gene regulatory elements in mammals that can overcome the highly repressive effects normally associated with heterochromatic transgene locations (for example the centromere) in mice1,2,3. Deletion of essential LCR sequences renders the cognate gene susceptible to this form of repression, so a proportion of the cells from transgenic mice that would normally express the transgene are silenced—a phenomenon known as position effect variegation4,5,6 (PEV). We show here that PEV can also occur when the transgene is non-centromeric and that the extent of variegation can be developmentally regulated. Furthermore, by overexpressing a mammalian homologue (M31) of Drosophila melanogaster heterochromatin protein 1 (HP1; refs 7,8) in transgenic mouse lines that exhibit PEV, it is possible to modify the proportion of cells that silence the transgene in a dose-dependent manner. Thus, we show M31 overexpression to have two contrasting effects which are dependent on chromosomal context: (i) it enhanced PEV in those lines with centromeric or pericentromeric transgene locations; and (ii) it suppressed PEV when the transgene was non-centromeric. Our results indicate that components or modifiers of heterochromatin may have a chromosomal-context-dependent role in gene silencing and activation decisions in mammals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: M31 transgenic mice overexpress M31 protein to different extents.
Figure 2: M31 overexpression enhances PEV when the transgene is pericentromeric.
Figure 3: The silencing of the CD2 transgene in thymocytes from CD2 1.
Figure 4: M31 overexpression suppresses PEV when the transgene is in a non-centromeric location.
Figure 5: The chromosomal location of the CD2 transgene influences its response to M31 overexpression.

Similar content being viewed by others

References

  1. Grosveld, F., van Assendelft, G.B., Greaves, D.R. & Kollias, G. Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell 51, 975– 985 (1987).

    Article  CAS  Google Scholar 

  2. Milot, E. et al. Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. Cell 87, 105– 114 (1996).

    Article  CAS  Google Scholar 

  3. Festenstein, R. et al. Locus control region function and heterochromatin-induced position effect variegation. Science 271, 1123–1125 (1996).

    Article  CAS  Google Scholar 

  4. Henikoff, S. Position effect variegation after 60 years. Trends Genet. 6, 422–426 (1990).

    Article  CAS  Google Scholar 

  5. Singh, P.B. Molecular mechanisms of cellular determination: their relation to chromatin structure. J. Cell Sci. 107, 2653– 2668 (1994).

    CAS  PubMed  Google Scholar 

  6. Elgin, S.C. Heterochromatin and gene regulation in Drosophila. Curr. Opin. Genet. Dev. 6, 193–202 (1996).

    Article  CAS  Google Scholar 

  7. Singh, P.B. et al. A sequence motif found in a Drosophila heterochromatin protein is conserved in animals and plants. Nucleic Acids Res. 19, 789–794 (1991).

    Article  CAS  Google Scholar 

  8. Eissenberg, J.C., Morris, G.D., Reuter, G. & Hartnett, T. The heterochromatin-associated protein HP-1 is an essential protein in Drosophila with dosage-dependent effects on position effect variegation. Genetics 131, 345–352 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Reuter, G. & Spierer, P. Position effect variegation and chromatin proteins. Bioessays 14, 605– 612 (1992).

    Article  CAS  Google Scholar 

  10. Locke, J., Kotarski, M.A. & Tartof, K.D. Dosage-dependent modifiers of positional effect variegation in Drosophila and a mass action model that explains their effect. Genetics 120, 181–198 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Aparicio, O.M. & Gottschling, D.E. Overcoming telomeric silencing: a trans-activator competes to establish gene expression in a cell cycle-dependent way. Genes Dev. 8, 1133–1146 (1994).

    Article  CAS  Google Scholar 

  12. Weintraub, H. Formation of stable transcription complexes as assayed by analysis of individual templates. Proc. Natl Acad. Sci. USA 85, 5819–5823 (1988).

    Article  CAS  Google Scholar 

  13. Walters, M.C. et al. Enhancers increase the probability but not the level of gene expression. Proc. Natl Acad. Sci. USA 92, 7125–7129 (1995).

    Article  CAS  Google Scholar 

  14. Boyes, J. & Felsenfeld, G. Tissue-specific factors additively increase the probability of the all- or-none formation of a hypersensitive site. EMBO J. 15, 2496– 2507 (1996).

    Article  CAS  Google Scholar 

  15. Saunders, W.S. et al. Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity. J. Cell Sci. 104, 573– 582 (1993).

    PubMed  Google Scholar 

  16. Wreggett, K.A. et al. A mammalian homologue of Drosophila heterochromatin protein 1 (HP1) is a component of constitutive heterochromatin. Cytogenet. Cell. Genet. 66, 99–103 (1994).

    Article  CAS  Google Scholar 

  17. Brown, K.E. et al. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell 91, 845–854 (1997).

    Article  CAS  Google Scholar 

  18. Le Douarin, B. et al. A possible involvement of TIF1 α and TIF1 β in the epigenetic control of transcription by nuclear receptors. EMBO J. 15, 6701–6715 (1996).

    Article  CAS  Google Scholar 

  19. Zhumabekov, T., Corbella, P., Tolaini, M. & Kioussis, D. Improved version of a human CD2 minigene based vector for T cell-specific expression in transgenic mice. J. Immunol. Methods 185, 133–140 (1995).

    Article  CAS  Google Scholar 

  20. Garrick, D., Fiering, S., Martin, D.I. & Whitelaw, E. Repeat-induced gene silencing in mammals. Nature Genet. 18, 56–59 (1998).

    Article  CAS  Google Scholar 

  21. Mamalaki, C. et al. Thymic depletion and peripheral activation of class I major histocompatibility complex-restricted T cells by soluble peptide in T-cell receptor transgenic mice. Proc. Natl Acad. Sci. USA 89, 11342–11346 (1992).

    Article  CAS  Google Scholar 

  22. Weiler, K.S. & Wakimoto, B.T. Heterochromatin and gene expression in Drosophila. Annu. Rev. Genet. 29, 577 –605 (1995).

    Article  CAS  Google Scholar 

  23. Lu, B.Y., Ma, J. & Eissenberg, J.C. Developmental regulation of heterochromatin-mediated gene silencing in Drosophila. Development 125, 2223–2234 (1998).

    CAS  PubMed  Google Scholar 

  24. Ye, Q., Callebaut, I., Pezhman, A., Courvalin, J.C. & Worman, H.J. Domain-specific interactions of human HP1-type chromodomain proteins and inner nuclear membrane protein LBR. J. Biol. Chem. 272, 14983– 14989 (1997).

    Article  CAS  Google Scholar 

  25. Singh, P.B. & Huskisson, N.S. Chromatin complexes as aperiodic microcrystalline arrays that regulate genome organisation and expression. Dev. Genet. 22, 85–99 (1998).

    Article  CAS  Google Scholar 

  26. Milot, E., Fraser, P. & Grosveld, F. Position effects and genetic disease. Trends Genet. 12, 123–126 (1996).

    Article  CAS  Google Scholar 

  27. Kleinjan, D.J. & van Heyningen, V. Position effect in human genetic disease. Hum. Mol. Genet. 7 , 1611–1618 (1998).

    Article  CAS  Google Scholar 

  28. Shi, Y.P. et al. FISH probes for mouse chromosome identification. Genomics 45, 42–47 (1997).

    Article  CAS  Google Scholar 

  29. Greaves, D.R., Wilson, F., Lang, G. & Kioussis, D. Human CD2 3′-flanking sequences confer high-level T-cell specific position independent gene expression in transgenic mice. Cell 56, 979 (1989).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank N. Dillon for supplying the mouse γ-satellite probe, A. Fischer for help with the P1 chromosomal probes, S. Uribe-Lewis for technical assistance and M. Burke for secretarial assistance. This work was partially funded by a European Commission Biotechnology Network grant (pl 970203). R.F. is an MRC (UK) Senior Fellow.

Author information

Authors and Affiliations

  1. Division of Molecular Immunology, National Institute for Medical Research, London, UK

    Richard Festenstein, Soheila Sharghi-Namini, Kathleen Roderick, Mauro Tolaini, Trisha Norton, Alexander Saveliev & Dimitris Kioussis

  2. Department of Medicine, Gene Control Mechanisms and Disease, Imperial College of Science Technology and Medicine, MRC Clinical Sciences Centre, Hammersmith Hospital, London, UK

    Richard Festenstein & Alexander Saveliev

  3. Medical Research Council Human Biochemical Genetics Unit, Galton Laboratory, University College, London, UK

    Margaret Fox

  4. Chromatin Function Laboratory, The Babraham Institute , Cambridge, UK

    Prim Singh

  5. Nuclear Reprogramming Laboratory, Roslin Institute (Edinburgh), Midlothian, Scotland

    Prim Singh

Authors
  1. Richard Festenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Soheila Sharghi-Namini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margaret Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathleen Roderick
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mauro Tolaini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Trisha Norton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexander Saveliev
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dimitris Kioussis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Prim Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard Festenstein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Festenstein, R., Sharghi-Namini, S., Fox, M. et al. Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal-context- dependent manner. Nat Genet 23, 457–461 (1999). https://doi.org/10.1038/70579

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/70579

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing