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 demethylation by a family of JmjC domain-containing proteins

Nature volume 439, pages 811–816 (2006)Cite this article

Abstract

Covalent modification of histones has an important role in regulating chromatin dynamics and transcription. Whereas most covalent histone modifications are reversible, until recently it was unknown whether methyl groups could be actively removed from histones. Using a biochemical assay coupled with chromatography, we have purified a novel JmjC domain-containing protein, JHDM1 (JmjC domain-containing histone demethylase 1), that specifically demethylates histone H3 at lysine 36 (H3-K36). In the presence of Fe(ii) and α-ketoglutarate, JHDM1 demethylates H3-methyl-K36 and generates formaldehyde and succinate. Overexpression of JHDM1 reduced the level of dimethyl-H3-K36 (H3K36me2) in vivo. The demethylase activity of the JmjC domain-containing proteins is conserved, as a JHDM1 homologue in Saccharomyces cerevisiae also has H3-K36 demethylase activity. Thus, we identify the JmjC domain as a novel demethylase signature motif and uncover a protein demethylation mechanism that is conserved from yeast to human.

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: Identification of a demethylase activity in HeLa cells.
Figure 2: Purification and identification of a histone demethylase activity.
Figure 3: Characterization of the histone demethylase JHDM1A/FBXL11.
Figure 4: Flag–JHDM1A-mediated histone demethylation generates formaldehyde and succinate.
Figure 5: The S. cerevisiae JHDM1 homologue exhibits H3-K36 demethylase activity.

Similar content being viewed by others

References

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

    Article  ADS  CAS  Google Scholar 

  2. 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 

  3. Margueron, R., Trojer, P. & Reinberg, D. The key to development: interpreting the histone code? Curr. Opin. Genet. Dev. 15, 163–176 (2005)

    Article  CAS  Google Scholar 

  4. Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nature Rev. Mol. Cell Biol. 6, 838–849 (2005)

    Article  CAS  Google Scholar 

  5. 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 

  6. Wang, H. et al. mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol. Cell 12, 475–487 (2003)

    Article  CAS  Google Scholar 

  7. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004)

    Article  CAS  Google Scholar 

  8. Hakimi, M. A. et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci. USA 99, 7420–7425 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Shi, Y. et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422, 735–738 (2003)

    Article  ADS  CAS  Google Scholar 

  10. You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST-human histone deacetylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001)

    Article  ADS  CAS  Google Scholar 

  11. Falnes, P. O., Johansen, R. F. & Seeberg, E. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli. Nature 419, 178–182 (2002)

    Article  ADS  CAS  Google Scholar 

  12. Trewick, S. C., Henshaw, T. F., Hausinger, R. P., Lindahl, T. & Sedgwick, B. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage. Nature 419, 174–178 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Wang, H. et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 293, 853–857 (2001)

    Article  ADS  CAS  Google Scholar 

  14. Carr, S. et al. The need for guidelines in publication of peptide and protein identification data: Working Group on Publication Guidelines for Peptide and Protein Identification Data. Mol. Cell. Proteomics 3, 531–533 (2004)

    Article  CAS  Google Scholar 

  15. Cenciarelli, C. et al. Identification of a family of human F-box proteins. Curr. Biol. 9, 1177–1179 (1999)

    Article  CAS  Google Scholar 

  16. Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J. & Harper, J. W. A family of mammalian F-box proteins. Curr. Biol. 9, 1180–1182 (1999)

    Article  CAS  Google Scholar 

  17. Clissold, P. M. & Ponting, C. P. JmjC: cupin metalloenzyme-like domains in jumonji, hairless and phospholipase A2β. Trends Biochem. Sci. 26, 7–9 (2001)

    Article  CAS  Google Scholar 

  18. Elkins, J. M. et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1α. J. Biol. Chem. 278, 1802–1806 (2003)

    Article  CAS  Google Scholar 

  19. Ayoub, N. et al. A novel jmjC domain protein modulates heterochromatization in fission yeast. Mol. Cell. Biol. 23, 4356–4370 (2003)

    Article  CAS  Google Scholar 

  20. Trewick, S. C., McLaughlin, P. J. & Allshire, R. C. Methylation: lost in hydroxylation? EMBO Rep. 6, 315–320 (2005)

    Article  CAS  Google Scholar 

  21. Cuthbert, G. L. et al. Histone deimination antagonizes arginine methylation. Cell 118, 545–553 (2004)

    Article  CAS  Google Scholar 

  22. Wang, Y. et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279–283 (2004)

    Article  ADS  CAS  Google Scholar 

  23. Kubicek, S. & Jenuwein, T. A crack in histone lysine methylation. Cell 119, 903–906 (2004)

    Article  CAS  Google Scholar 

  24. Wysocka, J., Milne, T. A. & Allis, C. D. Taking LSD1 to a new high. Cell 122, 654–658 (2005)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  26. Zhang, X. et al. Structural basis for the product specificity of histone lysine methyltransferases. Mol. Cell 12, 177–185 (2003)

    Article  Google Scholar 

  27. Kleeberg, U. & Klinger, W. Sensitive formaldehyde determination with Nash's reagent and a ‘tryptophan reaction’. J. Pharmacol. Methods 8, 19–31 (1982)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Lacomis and G. Boysen for help with mass spectrometry; B. Strahl, T. Jenuwein, Y. Shinkai and A. Verreault for reagents; R. Cao for the EZH2 complex; and R. Klose for critical reading of the manuscript. This work was supported by NIH grants to Y.Z., P.T. and C.H.B. Y.Z. is an Investigator of the Howard Hughes Medical Institute. Author Contributions Y.Z. designed the experimental strategy and wrote the paper; Y.T. worked out the details of the assay and performed most of the experiments; J.F. analysed the yeast protein; H.E.-B., M.E.W., C.H.B. and P.T. performed mass spectrometric analysis.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute,

    Yu-ichi Tsukada, Jia Fang & Yi Zhang

  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, 27599-7295, Chapel Hill, USA

    Yu-ichi Tsukada, Jia Fang, Maria E. Warren, Christoph H. Borchers & Yi Zhang

  3. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA

    Hediye Erdjument-Bromage & Paul Tempst

Authors
  1. Yu-ichi Tsukada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hediye Erdjument-Bromage
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria E. Warren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christoph H. Borchers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul Tempst
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Zhang.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1–9. (PDF 4512 kb)

Supplementary Figure Legends

Text to accompany the above Supplementary Figures. (DOC 28 kb)

Supplementary Methods

Detailed description of the experimental methods used in this study. (DOC 75 kb)

Supplementary Notes

Bibliography of references cited in Supplementary Information. (DOC 23 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsukada, Yi., Fang, J., Erdjument-Bromage, H. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006). https://doi.org/10.1038/nature04433

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04433

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