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J. Biol. Chem., Vol. 281, Issue 13, 8476-8485, March 31, 2006

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Histone H3 Lysine 9 Methyltransferase G9a Is a Transcriptional Coactivator for Nuclear Receptors^*

David Y. Lee¹, Jeffrey P. Northrop, Min-Hao Kuo, and Michael R. Stallcup²

From the Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90089 and the Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824

Methylation of Lys-9 of histone H3 has been associated with repression of transcription. G9a is a histone H3 Lys-9 methyltransferase localized in euchromatin and acts as a corepressor for specific transcription factors. Here we demonstrate that G9a also functions as a coactivator for nuclear receptors, cooperating synergistically with nuclear receptor coactivators glucocorticoid receptor interacting protein 1, coactivator-associated arginine methyltransferase 1 (CARM1), and p300 in transient transfection assays. This synergy depends strongly on the arginine-specific protein methyltransferase activity of CARM1 but does not absolutely require the enzymatic activity of G9a and is specific to CARM1 and G9a among various protein methyltransferases. Reduction of endogenous G9a diminished hormonal activation of an endogenous target gene by the androgen receptor, and G9a associated with regulatory regions of this same gene. G9a fused to Gal4 DNA binding domain can repress transcription in a lysine methyltransferase-dependent manner; however, the histone modifications associated with transcriptional activation can inhibit the methyltransferase activity of G9a. These findings suggest a link between histone arginine and lysine methylation and a mechanism for controlling whether G9a functions as a corepressor or coactivator.

Received for publication, October 12, 2005 , and in revised form, January 10, 2006.

^* This work was supported in part by National Institutes of Health Grant DK55274 (to M. R. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Supported by a predoctoral fellowship from National Institutes of Health Training Grant DE07211.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Southern California, 1333 San Pablo St., MCA-51A, Los Angeles, CA 90089-9151. Tel.: 323-442-1289; Fax: 323-442-1224; E-mail: stallcup{at}usc.edu.

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