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, Achim Leutz

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)26357-26363
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number39
DOIs
StatePublished - 26 Sep 2008

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