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LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription

Naturevolume 437pages436439 (2005) | Download Citation

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Abstract

Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor1. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues2. Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110)3 co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.

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Acknowledgements

We thank T. Benzing, F. Claessens, T. Jenuwein, Z. Sun and D. Trono for providing reagents. We are obliged to the members of the Schüle laboratory for discussions. We thank K. Fischer, P. Kahl and L. Heukamp for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe to R.S.

Author information

Author notes

  1. Melanie Wissmann and Na Yin: *These authors contributed equally to this work

Affiliations

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

    • Eric Metzger
    • , Melanie Wissmann
    • , Na Yin
    • , Judith M. Müller
    • , Thomas Günther
    •  & Roland Schüle
  2. Max-Planck-Institut für Immunbiologie, Stübeweg 51, 79108, Freiburg, Germany

    • Robert Schneider
  3. Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Maulbeerstrasse 66, 4058, Basel, Switzerland

    • Antoine H. F. M. Peters
  4. Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

    • Reinhard Buettner

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

Corresponding author

Correspondence to Roland Schüle.

Supplementary information

  1. Supplementary Notes

    Contains Supplementary Methods (plasmids, immunofluorescence, in vitro pull-down assays, mRNAanalyses, tandem affinity purification) and the legends for the Supplementary Figures. (DOC 41 kb)

  2. Supplementary Figure S1

    a, Coomassie blue staining reveals that LSD1 (arrow) is co-purified with TAP-FHL2 (arrow) during tandem affinity purification. b, Western blot analysis using -LSD1 antibody. (PDF 113 kb)

  3. Supplementary Figure S2

    LSD1 expression analyses. (PDF 88 kb)

  4. Supplementary Figure S3

    LSD1 interacts with chromatin. (PDF 82 kb)

  5. Supplementary Figure S4

    LNCaP cells were incubated with or without R1881 and treated with or without pargyline. (PDF 229 kb)

  6. Supplementary Figure S5

    siRNA mediated knockdown of LSD1. (PDF 52 kb)

  7. Supplementary Figure S6a-h

    Specificity of LSD1 in the control of AR-induced transcriptional activity. (PDF 15 kb)

  8. Supplementary Figure S6i-k

    Specificity of LSD1 in the control of AR-induced transcriptional activity. (PDF 8 kb)

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DOI

https://doi.org/10.1038/nature04020

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