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:

Evidence for the existence of an HP1-mediated subcode within the histone code

Nature Cell Biology volume 8, pages 407–415 (2006)Cite this article

Abstract

Currently, the mammalian heterochromatic proteins HP1α, HP1β and the pan-nuclear HP1γ are considered 'gatekeepers' of methyl-K9-H3-mediated silencing. Understanding how the binding of these proteins to post-translationally modified histones is switched on and off will further our knowledge of how the histone code is modulated. Here, we report that all three HP1 isoforms can be extensively modified, similar to histones, suggesting that the silencing of gene expression may be further regulated beyond the histone code. To assess the potential impact of these modifications, we analysed the phosphorylation of HP1γ at Ser 83 as a 'model modification'. We demonstrate that P-Ser 83-HP1γ has an exclusively euchromatic localization, interacts with Ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation. These observations predict that regulation of silencing by methyl-K9-H3 through modification of mammalian HP1 proteins may be more complex than previously thought and suggests the existence of an HP1-mediated 'silencing subcode' that underlies the instructions of the histone code.

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: Human HP1 isoforms undergo specific modifications.
Figure 2: Immunolocalization of P-Ser 83-HP1γ in euchromatin marks a distinct subpopulation of HP1γ.
Figure 3: Interaction of P-Ser 83-HP1γ with Ku70.
Figure 4: C-terminal PXVXL domain-independent interaction of Ku70 with P-Ser 83-HP1γ and analysis of P-Ser 83-HP1γ interaction with Ku70.
Figure 5: Functional characterization of Ser 83 phosphorylation in vivo.

Similar content being viewed by others

References

  1. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Eissenberg, J. C. Molecular biology of the chromo domain: an ancient chromatin module comes of age. Gene 275, 19–29 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Lachner, M. et al. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Minc, E., Courvalin, J. C. & Buendia, B. HP1γ associates with euchromatin and heterochromatin in mammalian nuclei and chromosomes. Cytogenet. Cell Genet. 90, 279–284 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Eissenberg, J. C., Ge, Y. W. & Hartnett, T. Increased phosphorylation of HP1, a heterochromatin-associated protein of Drosophila, is correlated with heterochromatin assembly. J. Biol. Chem. 269, 21315–21321 (1994).

    CAS  PubMed  Google Scholar 

  7. Huang, D. W. et al. Distinct cytoplasmic and nuclear fractions of Drosophila heterochromatin protein 1: their phosphorylation levels and associations with origin recognition complex proteins. J. Cell Biol. 142, 307–318 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhao, T. & Eissenberg, J. C. Phosphorylation of heterochromatin protein 1 by casein kinase II is required for efficient heterochromatin binding in Drosophila. J. Biol. Chem. 274, 15095–15100 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Minc, E. et al. Localization and phosphorylation of HP1 proteins during the cell cycle in mammalian cells. Chromosoma 108, 220–234 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Koike, N. et al. Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1(1). FEBS Lett. 467, 17–21 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Zhao, T., Heyduk, T. & Eissenberg, J. C. Phosphorylation site mutations in heterochromatin protein 1 (HP1) reduce or eliminate silencing activity. J. Biol. Chem. 276, 9512–9518 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Badugu, R., Yoo, Y., Singh, P. B. & Kellum, R. Mutations in the heterochromatin protein 1 (HP1) hinge domain affect HP1 protein interactions and chromosomal distribution. Chromosoma 113, 370–384 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Zhou, X. M. & Fishman, P. H. Desensitization of the human β1-adrenergic receptor. Involvement of the cyclic AMP-dependent but not a receptor-specific protein kinase. J. Biol. Chem. 266, 7462–7468 (1991).

    CAS  PubMed  Google Scholar 

  14. Vakoc, C. R., Mandat, S. A., Olenchock, B. A. & Blobel, G. A. Histone H3 lysine 9 methylation and HP1gamma are associated with transcription elongation through mammalian chromatin. Mol. Cell 19, 381–391 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Brasher, S. V. et al. The structure of mouse HP1 suggests a unique mode of single peptide recognition by the shadow chromo domain dimer. EMBO J. 19, 1587–1597 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cowieson, N. P., Partridge, J. F., Allshire, R. C. & McLaughlin, P. J. Dimerisation of a chromo shadow domain and distinctions from the chromodomain as revealed by structural analysis. Curr. Biol. 10, 517–525 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Smothers, J. F. & Henikoff, S. The HP1 chromo shadow domain binds a consensus peptide pentamer. Curr. Biol. 10, 27–30 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Gaudin, V. et al. Mutations in LIKE HETEROCHROMATIN PROTEIN 1 affect flowering time and plant architecture in Arabidopsis. Development 128, 4847–4858 (2001).

    CAS  PubMed  Google Scholar 

  19. Thiru, A. et al. Structural basis of HP1–PXVXL motif peptide interactions and HP1 localisation to heterochromatin. EMBO J. 23, 489–499 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Song, K., Jung, Y., Jung, D. & Lee, I. Human Ku70 interacts with heterochromatin protein 1α. J. Biol. Chem. 276, 8321–8327 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Gebelein, B. & Urrutia, R. Sequence-specific transcriptional repression by KS1, a multiple-zinc-finger-Kruppel-associated box protein. Mol. Cell Biol. 21, 928–939 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Morris, D. P., Michelotti, G. A. & Schwinn, D. A. Evidence that phosphorylation of the RNA polymerase II carboxyl-terminal repeats is similar in yeast and humans. J. Biol. Chem. 280, 31368–31377 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank S. Delgado and T. Clark for the significant technical assistance they provided for experiments that led to the results shown in Figs 1 and 4, respectively. This work was supported by funding from the National Institutes of Health (grants DK52913 and DK56620) and the Mayo Kogod Center for Aging Research (R. U.). G. L. was supported by the Mayo Clinic National Institutes of Health training grant in Digestive Diseases.

Author information

Authors and Affiliations

  1. Department of Medicine, Gastroenterology Research Unit, and Mayo Clinic Cancer Center, Rochester, 55605, MN, USA

    Gwen Lomberk, Debora Bensi, Martín E. Fernandez-Zapico & Raul Urrutia

Authors
  1. Gwen Lomberk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debora Bensi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martín E. Fernandez-Zapico
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Raul Urrutia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raul Urrutia.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3 and S4 (PDF 429 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lomberk, G., Bensi, D., Fernandez-Zapico, M. et al. Evidence for the existence of an HP1-mediated subcode within the histone code. Nat Cell Biol 8, 407–415 (2006). https://doi.org/10.1038/ncb1383

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1383

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