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Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain

Abstract

Heterochromatin protein 1 (HP1) is localized at heterochromatin sites where it mediates gene silencing1,2. The chromo domain of HP1 is necessary for both targeting and transcriptional repression3,4. In the fission yeast Schizosaccharomyces pombe, the correct localization of Swi6 (the HP1 equivalent) depends on Clr4, a homologue of the mammalian SUV39H1 histone methylase5,6. Both Clr4 and SUV39H1 methylate specifically lysine 9 of histone H3 (ref. 6). Here we show that HP1 can bind with high affinity to histone H3 methylated at lysine 9 but not at lysine 4. The chromo domain of HP1 is identified as its methyl-lysine-binding domain. A point mutation in the chromo domain, which destroys the gene silencing activity of HP1 in Drosophila3, abolishes methyl-lysine-binding activity. Genetic and biochemical analysis in S. pombe shows that the methylase activity of Clr4 is necessary for the correct localization of Swi6 at centromeric heterochromatin and for gene silencing. These results provide a stepwise model for the formation of a transcriptionally silent heterochromatin: SUV39H1 places a ‘methyl marker’ on histone H3, which is then recognized by HP1 through its chromo domain. This model may also explain the stable inheritance of the heterochromatic state.

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Figure 1: HP1 chromo domain binds methylated H3.
Figure 2: HP1 chromo domain specifically binds methylated Lys 9 of histone H3.
Figure 3: HP1 chromatin localization is dependent on binding to methylated K9 of H3.
Figure 4: Swi6 localization is dependent on the methylase activity of the Clr4 SET domain.
Figure 5

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References

  1. Eissenberg, J. C. & Elgin, S. C. R. The HP1 protein family: getting a grip on chromatin. Curr. Opin. Genet. Dev. 10, 204–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Eissenberg, J. C. et al. Mutation in a heterochromatin-specific chromosomal protein is associated with supression of position-effect variegation in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 87, 9923–9927 (1990).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Platero, J. S., Hartnett, T. & Eissenberg, J. C. Functional analysis of the chromo domain of HP1. EMBO J. 14, 3977–3986 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cavalli, G. & Paro, R. Chromo-domain proteins: linking chromatin structure to epigenetic regulation. Curr. Opin. Cell Biol. 10, 354–360 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Ekwall, K. et al. Mutations in the fission yeast silencing factors clr4+ and rik1+ disrupt the localisation of the chromo domain protein Swi6p and impair centromere function. J. Cell Sci. 109, 2637–2648 (1996).

    CAS  PubMed  Google Scholar 

  6. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Strahl, B. D. & Allis, C. D. The language of covalent histone modifcations. Nature 403, 41–45 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Jacobson, R. H., Ladurner, A. G., King, D. S. & Tijan, R. Structure and function of a human TAFII250 double bromodomain module. Science 288, 1422–1425 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Pak, D. T. S. et al. Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes. Cell 91, 311–323 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Ekwall, K., Olsson, T., Turner, B. M., Cranston, G. & Allshire, R. C. Transient inhibition of histone deacetylation alters the structural and functional imprint at fission yeast centromeres. Cell 91, 1021–1032 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Partridge, J. F., Borgstrom, B. & Allshire, R. C. Distinct protein interaction domains and protein spreading in a complex centromere. Genes Dev. 14, 783–791 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ekwall, K. et al. The chromodomain protein Swi6: a key component at fission yeast centromeres. Science 269, 1429–1431 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Bannister, A. J. & Kouzarides, T. The CBP co-activator is a histone acetyltransferase. Nature 384, 641–643 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  15. 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 

  16. Krude, T. Mimosine arrests proliferating human cells before onset of DNA replication in a dose-dependent manner. Exp. Cell Res. 247, 148–159 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Krude, T. Initiation of human DNA replication in vitro using nuclei from cells arrested at an initiation-competent state. J. Biol. Chem. 275, 13699–13707 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Allshire, R. C., Nimmo, E. R., Ekwall, K., Javerzat, J. P. & Cranston, G. Mutations derepressing silent centromeric domains in fission yeast disrupt chromosome segregation. Genes Dev. 9, 218–233 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Nimmo, E. R., Pidoux, A. L., Perry, P. E. & Allshire, R. C. Defective meiosis in telomere-silencing mutants of Schizosaccharomyces pombe. Nature 392, 825–828 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Allshire, R. C., Javerzat, J. P., Redhead, N. J. & Cranston, G. Position effect variegation at fission yeast centromeres. Cell 76, 157–169 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Thomas, J. O. in Chromatin, a Practical Approach (ed. Gould, H. J.) 1–34 (Oxford Univ. Press, 1998).

    Google Scholar 

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Acknowledgements

We thank E. Laue and N. Murzina for his-HP1 clones, M33 and Mi2 clones, and for discussions on structure, and P. Chambon for GST-HP1 clones. We also thank D. Durocher for advice with SPR, T. Krude for guidance on nuclear preparations and M. Ruas for preparing some proteins. We are grateful to E. Andrews for help in the preparation of nucleosomes, and to E. Nimmo and P. Lord for the clr4-G341D allele. Peptides were synthesized by G. Bloomberg, Bristol University. This work was funded by a Cancer Research Campaign programme grant to T.K. and Medical Research Council core support to R.A. J.O.T. thanks the BBSRC for support.

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Correspondence to Tony Kouzarides.

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Bannister, A., Zegerman, P., Partridge, J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001). https://doi.org/10.1038/35065138

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