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J. Biol. Chem., Vol. 283, Issue 39, 26357-26363, September 26, 2008

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G9a-mediated Lysine Methylation Alters the Function of CCAAT/Enhancer-binding Protein-β^*

Ole Pless, Elisabeth Kowenz-Leutz, Maria Knoblich, Jörn Lausen, Michael Beyermann^¶, Martin J. Walsh^||, and Achim Leutz¹

From the Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin, and the ^¶Leibniz-Institut for Molecular Pharmacology, Robert-Rössle-Strasse 10, D-13125 Berlin, Germany, the Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt/Main, Germany, and the ^||Departments of Pediatrics and Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029

The functional capacity of the transcriptional regulatory CCAAT/enhancer-binding protein-β (C/EBPβ) is governed by protein interactions and post-translational protein modifications. In a proteome-wide interaction screen, the histone-lysine N-methyltransferase, H3 lysine 9-specific 3 (G9a), was found to directly interact with the C/EBPβ transactivation domain (TAD). Binding between G9a and C/EBPβ was confirmed by glutathione S-transferase pulldown and co-immunoprecipitation. Metabolic labeling showed that C/EBPβ is post-translationally modified by methylation in vivo. A conserved lysine residue in the C/EBPβ TAD served as a substrate for G9a-mediated methylation. G9a, but not a methyltransferase-defective G9a mutant, abrogated the transactivation potential of wild type C/EBPβ. A C/EBPβ TAD mutant that contained a lysine-to-alanine exchange was resistant to G9a-mediated inhibition. Moreover, the same mutation conferred super-activation of a chromatin-embedded, endogenous C/EBPβ target gene. Our data identify C/EBPβ as a direct substrate of G9a-mediated post-translational modification that alters the functional properties of C/EBPβ during gene regulation.

Received for publication, March 17, 2008 , and in revised form, July 21, 2008.

^* 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 Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 49-30-9406-3735; Fax: 49-30-9406-3298; E-mail: aleutz{at}mdc-berlin.de.

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