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Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression

Nature Cell Biology volume 9, pages 347353 (2007) | Download Citation

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Abstract

Posttranslational modifications of histones, such as methylation, regulate chromatin structure and gene expression1. Recently, lysine-specific demethylase 1 (LSD1)2, the first histone demethylase, was identified. LSD1 interacts with the androgen receptor and promotes androgen-dependent transcription of target genes by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9)3 only. Here, we identify the Jumonji C (JMJC)4 domain-containing protein JMJD2C5,6 as the first histone tridemethylase regulating androgen receptor function. JMJD2C interacts with androgen receptor in vitro and in vivo. Assembly of ligand-bound androgen receptor and JMJD2C on androgen receptor-target genes results in demethylation of trimethyl H3K9 and in stimulation of androgen receptor-dependent transcription. Conversely, knockdown of JMJD2C inhibits androgen-induced removal of trimethyl H3K9, transcriptional activation and tumour cell proliferation. Importantly, JMJD2C colocalizes with androgen receptor and LSD1 in normal prostate and in prostate carcinomas. JMJD2C and LSD1 interact and both demethylases cooperatively stimulate androgen receptor-dependent gene transcription. In addition, androgen receptor, JMJD2C and LSD1 assemble on chromatin to remove methyl groups from mono, di and trimethylated H3K9. Thus, our data suggest that specific gene regulation requires the assembly and coordinate action of demethylases with distinct substrate specificities.

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Acknowledgements

We thank S. Gray for generously providing reagents. We thank K. Fischer, L. Walz, F. Klott and S. Vomstein for excellent technical assistance. We are obliged to M. Hoffmann and A. Schwentek from the sequencing core facility. We thank M. Follo for help with editing the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 747/P2, Schu 688/7-1, and Schu 688/9-1), the Dr. Hans Messner-Stiftung, and the Deutsche Krebshilfe (10-2019-Bu I) to R.S.

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Affiliations

  1. Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.

    • Melanie Wissmann
    • , Na Yin
    • , Judith M. Müller
    • , Holger Greschik
    • , Thomas Günther
    • , Eric Metzger
    •  & Roland Schüle
  2. Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Dr. Bohrgasse 7, 1030 Vienna, Austria.

    • Barna D. Fodor
    •  & Thomas Jenuwein
  3. Max-Planck-Institut für Immunbiologie, Stübeweg 51, 79108 Freiburg, Germany.

    • Christine Vogler
    •  & Robert Schneider
  4. Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.

    • Reinhard Buettner

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The authors declare no competing financial interests.

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Correspondence to Roland Schüle.

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DOI

https://doi.org/10.1038/ncb1546

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