The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36 (original) (raw)

Nature volume 442, pages 312–316 (2006)Cite this article

Abstract

Post-translational modification of chromatin has profound effects on many biological processes including transcriptional regulation, heterochromatin organization, and X-chromosome inactivation1,2. Recent studies indicate that methylation on specific histone lysine (K) residues participates in many of these processes3. Lysine methylation occurs in three distinct states, having either one (me1), two (me2) or three (me3) methyl groups attached to the amine group of the lysine side chain. These differences in modification state have an important role in defining how methylated chromatin is recognized and interpreted4,5,6. Until recently, histone lysine methylation was considered a stable modification7,8, but the identification of histone demethylase enzymes has demonstrated the reversibility of this epigenetic mark9,10,11. So far, all characterized histone demethylases show enzymatic activity towards lysine residues modified in the me1 or me2 state9,10,11, leaving open the possibility that me3 constitutes an irreversible modification. Here we demonstrate that JHDM3A (jumonji C (JmjC)-domain-containing histone demethylase 3A; also known as JMJD2A) is capable of removing the me3 group from modified H3 lysine 9 (H3K9) and H3 lysine 36 (H3K36). Overexpression of JHDM3A abrogates recruitment of HP1 (heterochromatin protein 1) to heterochromatin, indicating a role for JHDM3A in antagonizing methylated H3K9 nucleated events. siRNA-mediated knockdown of JHDM3A leads to increased levels of H3K9 methylation and upregulation of a JHDM3A target gene, ASCL2, indicating that JHDM3A may function in euchromatin to remove histone methylation marks that are associated with active transcription12.

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Acknowledgements

We thank J. Fang, B. Strahl, T. Jenuwein, L. Schmiedeberg, A. Verreault and Y. Shinkai for plasmids; X. Cheng and R. Cao for Dim5 protein and EZH2 complex, respectively; L. Lacomis for help with mass spectrometry; and technical assistance from C. Toumazou. This work was supported by NIH grants to Y.Z., P.T. and J.W. Y.Z. is an Investigator of the Howard Hughes Medical Institute. Author Contributions R.J.K. carried out most of the experiments in Figs 1–3and the Supplementary Figures; K.Y. generated recombinant protein; H.E.-B. and P.T. performed mass spectrometric analysis; Y.B., D.Z. and J.W. carried out the experiments in Fig. 4; R.J.K. and Y.Z. wrote the paper.

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Authors and Affiliations

  1. Howard Hughes Medical Institute,
    Robert J. Klose, Kenichi Yamane & Yi Zhang
  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7295, USA
    Robert J. Klose, Kenichi Yamane & Yi Zhang
  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Texas, 77030, Houston, USA
    Yangjin Bae, Dianzheng Zhang & Jiemin Wong
  4. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA
    Hediye Erdjument-Bromage & Paul Tempst

Authors

  1. Robert J. Klose
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  2. Kenichi Yamane
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  3. Yangjin Bae
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  4. Dianzheng Zhang
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  5. Hediye Erdjument-Bromage
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  6. Paul Tempst
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  7. Jiemin Wong
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  8. Yi Zhang
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Correspondence toYi Zhang.

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Klose, R., Yamane, K., Bae, Y. et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36.Nature 442, 312–316 (2006). https://doi.org/10.1038/nature04853

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Editorial Summary

Up to the mark

Two papers in this issue identify enzymes capable of demethylating a trimethyl group from the Lys 9 residue of histone H3 — a 'mark' required for the establishment of heterochromatin and previously considered stable. Cloos et al. show that GASC1, a member of the JMJD2 enzyme family, can disrupt heterochromatin structure when overexpressed and may contribute to tumour development. Klose et al. show that overexpression of JHDM3A, also a JMJD2-type enzyme, disrupts heterochromatin structure. It may function in euchromatin to regulate transcription.