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The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36

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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Figure 1: JMJD2A/JHDM3A is a histone H3K9/H3K36 demethylase capable of removing trimethyl-lysine.
Figure 2: JHDM3A requires the JmjC and JmjN domains to demethylate H3K9/H3K36 in vivo.
Figure 3: Overexpression of JHDM3A antagonizes HP1 recruitment to pericentric heterochromatin.
Figure 4: JHDM3A regulates H3K9/H3K36 methylation at a euchromatic target gene.

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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

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Supplementary Methods

Detailed description of the experimental methods used in this study. (DOC 50 kb)

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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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