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.

  • Hypothesis
  • Published:

Binary switches and modification cassettes in histone biology and beyond

Nature volume 425, pages 475–479 (2003)Cite this article

Abstract

An immense number of post-translational modifications on histone proteins have been described and additional sites of modification are still being uncovered. Whereas many direct and indirect connections between certain histone modifications and distinct biological phenomena have now been established, concepts for comprehending the extreme density and variety of these covalent modifications are lacking. Here, we formally introduce localized ‘binary switches’ and ‘modification cassettes’ as new concepts in histone biology, elucidating mechanisms that might govern the biological readout of distinct modification patterns. Specifically, our hypotheses provide missing models for the dynamic readout of stable histone modifications and offer explanations for several long-standing questions embedded in the literature. Our ideas might also apply to non-histone proteins and are open to direct experimental examination.

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: Dense clustering of histone marks.
Figure 2: Local binary switches.
Figure 3: Surveillance of putative ‘methyl/phos switches’ in core histones.
Figure 4: Putative ‘cassettes’ and ‘switches’ in histone and non-histone proteins.

Similar content being viewed by others

References

  1. Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448–453 (2003)

    Article  ADS  Google Scholar 

  2. Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000)

    Article  CAS  Google Scholar 

  3. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001)

    Article  CAS  Google Scholar 

  4. Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286–298 (2002)

    Article  CAS  Google Scholar 

  5. Pawson, T., Gish, G. D. & Nash, P. SH2 domains, interaction modules and cellular wiring. Trends Cell Biol. 11, 504–511 (2001)

    Article  CAS  Google Scholar 

  6. Schreiber, S. L. & Bernstein, B. E. Signaling network model of chromatin. Cell 111, 771–778 (2002)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  8. Zhang, K. et al. Identification of acetylation and methylation sites of histone H3 from chicken erythrocytes by high-accuracy matrix-assisted laser desorption ionization-time-of-flight, matrix-assisted laser desorption ionization-postsource decay, and nanoelectrospray ionization tandem mass spectrometry. Anal. Biochem. 306, 259–269 (2002)

    Article  CAS  Google Scholar 

  9. Zhang, L., Eugeni, E. E., Parthun, M. R. & Freitas, M. A. Identification of novel histone post-translational modifications by peptide mass fingerprinting. Chromosoma 112, 77–86 (2003)

    Article  CAS  Google Scholar 

  10. Fischle, W., Wang, Y. & Allis, C. D. Histone and chromatin cross-talk. Curr. Opin. Cell Biol. 15, 172–183 (2003)

    Article  CAS  Google Scholar 

  11. Festenstein, R. et al. Modulation of heterochromatin protein 1 dynamics in primary Mammalian cells. Science 299, 719–721 (2003)

    Article  ADS  CAS  Google Scholar 

  12. Cheutin, T. et al. Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science 299, 721–725 (2003)

    Article  ADS  CAS  Google Scholar 

  13. Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002)

    Article  CAS  Google Scholar 

  14. Ayyanathan, K. et al. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev. 17, 1855–1869 (2003)

    Article  CAS  Google Scholar 

  15. Li, Y., Danzer, J. R., Alvarez, P., Belmont, A. S. & Wallrath, L. L. Effects of tethering HP1 to euchromatic regions of the Drosophila genome. Development 130, 1817–1824 (2003)

    Article  CAS  Google Scholar 

  16. Berger, S. L. Histone modifications in transcriptional regulation. Curr. Opin. Genet. Dev. 12, 142–148 (2002)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  18. Jacobs, S. A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002)

    Article  ADS  CAS  Google Scholar 

  19. Nielsen, P. R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002)

    Article  ADS  CAS  Google Scholar 

  20. Kellum, R., Raff, J. W. & Alberts, B. M. Heterochromatin protein 1 distribution during development and during the cell cycle in Drosophila embryos. J. Cell Sci. 108, 1407–1418 (1995)

    CAS  PubMed  Google Scholar 

  21. Minc, E., Allory, Y., Worman, H. J., Courvalin, J. C. & Buendia, B. Localization and phosphorylation of HP1 proteins during the cell cycle in mammalian cells. Chromosoma 108, 220–234 (1999)

    Article  CAS  Google Scholar 

  22. Hsu, J. Y. et al. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102, 279–291 (2000)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Fischle, W. et al. Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by Polycomb and HP1 chromodomains. Genes Dev. 17, 1870–1881 (2003)

    Article  CAS  Google Scholar 

  25. Waterborg, J. H. Sequence analysis of acetylation and methylation in two histone H3 variants of alfalfa. J. Biol. Chem. 265, 17157–17161 (1990)

    CAS  PubMed  Google Scholar 

  26. Lachner, M., O'Sullivan, R. J. & Jenuwein, T. An epigenetic road map for histone lysine methylation. J. Cell Sci. 116, 2117–2124 (2003)

    Article  CAS  Google Scholar 

  27. Park, J. H., Cosgrove, M. S., Youngman, E., Wolberger, C. & Boeke, J. D. A core nucleosome surface crucial for transcriptional silencing. Nature Genet. 32, 273–279 (2002)

    Article  CAS  Google Scholar 

  28. Thompson, J. S., Snow, M. L., Giles, S., McPherson, L. E. & Grunstein, M. Identification of a functional domain within the essential core of histone H3 that is required for telomeric and HM silencing in Saccharomyces cerevisiae. Genetics 163, 447–452 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ng, H. H., Ciccone, D. N., Morshead, K. B., Oettinger, M. A. & Struhl, K. Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: a potential mechanism for position-effect variegation. Proc. Natl Acad. Sci. USA 100, 1820–1825 (2003)

    Article  ADS  CAS  Google Scholar 

  30. van Leeuwen, F., Gafken, P. R. & Gottschling, D. E. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002)

    Article  CAS  Google Scholar 

  31. Clayton, A. L., Rose, S., Barratt, M. J. & Mahadevan, L. C. Phosphoacetylation of histone H3 on c-fos- and c-jun-associated nucleosomes upon gene activation. EMBO J. 19, 3714–3726 (2000)

    Article  CAS  Google Scholar 

  32. Baarends, W. M. et al. Histone ubiquitination and chromatin remodeling in mouse spermatogenesis. Dev. Biol. 207, 322–333 (1999)

    Article  CAS  Google Scholar 

  33. Davie, J. R., Lin, R. & Allis, C. D. Timing of the appearance of ubiquitinated histones in developing new macronuclei of Tetrahymena thermophila. Biochem. Cell Biol. 69, 66–71 (1991)

    Article  CAS  Google Scholar 

  34. Fujitaki, J. M., Fung, G., Oh, E. Y. & Smith, R. A. Characterization of chemical and enzymatic acid-labile phosphorylation of histone H4 using phosphorus-31 nuclear magnetic resonance. Biochemistry 20, 3658–3664 (1981)

    Article  CAS  Google Scholar 

  35. Appella, E. & Anderson, C. W. Signaling to p53: breaking the posttranslational modification code. Pathol. Biol. (Paris) 48, 227–245 (2000)

    CAS  Google Scholar 

  36. Prives, C. & Manley, J. L. Why is p53 acetylated? Cell 107, 815–818 (2001)

    Article  CAS  Google Scholar 

  37. Brooks, C. L. & Gu, W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr. Opin. Cell Biol. 15, 164–171 (2003)

    Article  CAS  Google Scholar 

  38. Santos-Rosa, H. et al. Active genes are tri-methylated at K4 of histone H3. Nature 419, 407–411 (2002)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank all current and past members of the Allis laboratory for their input and support as well as many collaborators with whom we have worked or discussed our ideas. We are especially grateful to T. Jenuwein, D. Reinberg and M. Grunstein for discussions in the process of writing this article. We also thank D. F. Hunt and his laboratory as well as C. M. Barber for their groundbreaking work on the in vivo modification patterns of histones that spurred many of the ideas presented here. W.F. is a Robert Black fellow of the Damon Runyon Cancer Research Foundation. Work in the laboratory of C.D.A. is supported by several grants from the NIH.

Author information

Authors and Affiliations

  1. Laboratory of Chromatin Biology, The Rockefeller University, New York, New York, 10021, USA

    Wolfgang Fischle, Yanming Wang & C. David Allis

Authors
  1. Wolfgang Fischle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. David Allis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. David Allis.

Ethics declarations

Competing interests

A provisional US patent has been filed on this work at the University of Virginia. All co-authors and Don Hunt are listed as investors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fischle, W., Wang, Y. & David Allis, C. Binary switches and modification cassettes in histone biology and beyond. Nature 425, 475–479 (2003). https://doi.org/10.1038/nature02017

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02017

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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