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Molecular and Cellular Biology, June 2008, p. 3995-4003, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02030-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Transrepressive Function of TLX Requires the Histone Demethylase LSD1 {triangledown} ,{dagger}

Atsushi Yokoyama,1 Shinichiro Takezawa,1 Roland Schüle,2 Hirochika Kitagawa,1 and Shigeaki Kato1,3*

Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan,1 Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany,2 ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan3

Received 12 November 2007/ Returned for modification 5 January 2008/ Accepted 31 March 2008

TLX is an orphan nuclear receptor (also called NR2E1) that regulates the expression of target genes by functioning as a constitutive transrepressor. The physiological significance of TLX in the cytodifferentiation of neural cells in the brain is known. However, the corepressors supporting the transrepressive function of TLX have yet to be identified. In this report, Y79 retinoblastoma cells were subjected to biochemical techniques to purify proteins that interact with TLX, and we identified LSD1 (also called KDM1), which appears to form a complex with CoREST and histone deacetylase 1. LSD1 interacted with TLX directly through its SWIRM and amine oxidase domains. LSD1 potentiated the transrepressive function of TLX through its histone demethylase activity as determined by a luciferase assay using a genomically integrated reporter gene. LSD1 and TLX were recruited to a TLX-binding site in the PTEN gene promoter, accompanied by the demethylation of H3K4me2 and deacetylation of H3. Knockdown of either TLX or LSD1 derepressed expression of the endogenous PTEN gene and inhibited cell proliferation of Y79 cells. Thus, the present study suggests that LSD1 is a prime corepressor for TLX.

* Corresponding author. Mailing address: Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Phone: 81-3-5841-8478. Fax: 81-3-5841-8477. E-mail: uskato{at}mail.ecc.u-tokyo.ac.jp

{triangledown} Published ahead of print on 7 April 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2008, p. 3995-4003, Vol. 28, No. 12
0270-7306/08/$08.00+0     doi:10.1128/MCB.02030-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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