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.

  • Article
  • Published:

Histone H3 tail clipping regulates gene expression

Abstract

Induction of gene expression in yeast and human cells involves changes in the histone modifications associated with promoters. Here we identify a histone H3 endopeptidase activity in Saccharomyces cerevisiae that may regulate these events. The endopeptidase cleaves H3 after Ala21, generating a histone that lacks the first 21 residues and shows a preference for H3 tails carrying repressive modifications. In vivo, the H3 N terminus is clipped, specifically within the promoters of genes following the induction of transcription. H3 clipping precedes the process of histone eviction seen when genes become fully active. A truncated H3 product is not generated in yeast carrying a mutation of the endopeptidase recognition site (H3 Q19A L20A) and gene induction is defective in these cells. These findings identify clipping of H3 tails as a previously uncharacterized modification of promoter-bound nucleosomes, which may result in the localized clearing of repressive signals during the induction of gene expression.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: A histone H3 endopeptidase activity in S. cerevisiae.
Figure 2: The histone H3 endopeptidase is a serine protease with a preference for non activating marks.
Figure 3: The H3 endopeptidase is a serine protease.
Figure 4: Histone tails are removed before core depletion from promoters.
Figure 5: Histone H3 Q19A L20A mutation abrogates tail loss and causes transcription defects.

Similar content being viewed by others

References

  1. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  Google Scholar 

  2. Lee, C.K., Shibata, Y., Rao, B., Strahl, B.D. & Lieb, J.D. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat. Genet. 36, 900–905 (2004).

    Article  CAS  Google Scholar 

  3. Korber, P., Luckenbach, T., Blaschke, D. & Hörz, W. Evidence for histone eviction in trans upon induction of the yeast PHO5 promoter. Mol. Cell. Biol. 24, 10965–10974 (2004).

    Article  CAS  Google Scholar 

  4. Bernstein, B.E., Liu, C.L., Humphrey, E.L., Perlstein, E.O. & Schreiber, S.L. Global nucleosome occupancy in yeast. Genome Biol. 5, R62 (2004).

    Article  Google Scholar 

  5. Schermer, U.J., Korber, P. & Hörz, W. Histones are incorporated in trans during reassembly of the yeast PHO5 promoter. Mol. Cell 19, 279–285 (2005).

    Article  CAS  Google Scholar 

  6. Schwabish, M.A. & Struhl, K. Asf1 mediates histone eviction and deposition during elongation by RNA polymerase II. Mol. Cell 22, 415–422 (2006).

    Article  CAS  Google Scholar 

  7. English, C.M., Adkins, M.W., Carson, J.J., Churchill, M.E. & Tyler, J.K. Structural basis for the histone chaperone activity of Asf1. Cell 127, 495–508 (2006).

    Article  CAS  Google Scholar 

  8. Reinke, H. & Hörz, W. Histones are first hyperacetylated and then lose contact with the activated PHO5 promoter. Mol. Cell 11, 1599–1607 (2003).

    Article  CAS  Google Scholar 

  9. Elia, M.C. & Moudrianakis, E.N. Regulation of H2a-specific proteolysis by the histone H3:H4 tetramer. J. Biol. Chem. 263, 9958–9964 (1988).

    CAS  PubMed  Google Scholar 

  10. Kaul, R., Hoang, A., Yau, P., Bradbury, E.M. & Wenman, W.M. The chlamydial EUO gene encodes a histone H1-specific protease. J. Bacteriol. 179, 5928–5934 (1997).

    Article  CAS  Google Scholar 

  11. Allis, C.D., Allen, R.L., Wiggins, J.C., Chicoine, L.G. & Richman, R. Proteolytic processing of H1-like histones in chromatin: a physiologically and developmentally regulated event in Tetrahymena micronuclei. J. Cell Biol. 99, 1669–1677 (1984).

    Article  CAS  Google Scholar 

  12. Allis, C.D., Bowen, J.K., Abraham, G.N., Glover, C.V. & Gorovsky, M.A. Proteolytic processing of histone H3 in chromatin: a physiologically regulated event in Tetrahymena micronuclei. Cell 20, 55–64 (1980).

    Article  CAS  Google Scholar 

  13. Lin, R., Cook, R.G. & Allis, C.D. Proteolytic removal of core histone amino termini and dephosphorylation of histone H1 correlate with the formation of condensed chromatin and transcriptional silencing during Tetrahymena macronuclear development. Genes Dev. 5, 1601–1610 (1991).

    Article  CAS  Google Scholar 

  14. Bortvin, A. & Winston, F. Evidence that Spt6p controls chromatin structure by a direct interaction with histones. Science 272, 1473–1476 (1996).

    Article  CAS  Google Scholar 

  15. Liu, C.L. et al. Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS Biol. 3, e328 (2005).

    Article  Google Scholar 

  16. Duncan, E.M. et al. Cathepsin L proteolytically processes Histone H3 during embryonic stem cell differentiation. Cell 135, 284–294 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Shogren-Knaak, M.A. & Peterson, C.L. Creating designer histones by native chemical ligation. Methods Enzymol. 375, 62–76 (2004).

    Article  CAS  Google Scholar 

  19. Kizer, K.O., Xiao, T. & Strahl, B.D. Accelerated nuclei preparation and methods for analysis of histone modifications in yeast. Methods 40, 296–302 (2006).

    Article  CAS  Google Scholar 

  20. Altaf, M. et al. Interplay of chromatin modifiers on a short basic patch of histone H4 tail defines the boundary of telomeric heterochromatin. Mol. Cell 28, 1002–1014 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Xhemalce for constructive discussions, L. Packman for excellent assistance with peptide and calf H3 sequencing and A. Verreault (Institute for Research in Immunology and Cancer, Université de Montréal) for the gift of H3 and H4 antibodies. We are most grateful to M. Dickman, M. Vermeulen and M. Mann, H. Erdjument-Bromage, P. Tempst, S. Tully, B.F. Cravatt and S.Y. Peak-Chew for their attempts to identify the H3 endopeptidase by MS.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tony Kouzarides.

Ethics declarations

Competing interests

T.K. is a director of Abcam Plc.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Table 1 (PDF 1539 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santos-Rosa, H., Kirmizis, A., Nelson, C. et al. Histone H3 tail clipping regulates gene expression. Nat Struct Mol Biol 16, 17–22 (2009). https://doi.org/10.1038/nsmb.1534

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1534

This article is cited by

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