title: Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C).
abstract: Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 9 trimethylation (H3K9me3) are epigenetic marks with opposing roles in transcription regulation. Whereas colocalization of these modifications is generally excluded in the genome, how this preclusion is established remains poorly understood. Lysine demethylase 4C (KDM4C), an H3K9me3 demethylase, localizes predominantly to H3K4me3-containing promoters through its hybrid tandem tudor domain (TTD) (1, 2), providing a model for how these modifications might be excluded. We quantitatively investigated the contribution of the TTD to the catalysis of H3K9me3 demethylation by KDM4C and demonstrated that TTD-mediated recognition of H3K4me3 stimulates demethylation of H3K9me3 in cis on peptide and mononucleosome substrates. Our findings support a multivalent interaction mechanism, by which an activating mark, H3K4me3, recruits and stimulates KDM4C to remove the repressive H3K9me3 mark, thus facilitating exclusion. In addition, our work suggests that differential TTD binding properties across the KDM4 demethylase family may differentiate their targets in the genome.
authors.affiliation: From the Department of Cellular and Molecular Pharmacology, the Tetrad Graduate Program, and.
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Pack
authors.affiliation: From the Department of Cellular and Molecular Pharmacology, Yamamoto@ucsf.edu.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Yamamoto
authors.affiliation: From the Department of Cellular and Molecular Pharmacology, the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158 Danica.Fujimori@ucsf.edu.
authors.forename: Danica Galonić
authors.initials: DG
authors.lastname: Fujimori
mesh_terms: D002843:Chromatin / Q000502:physiology*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry*; D007700:Kinetics; D008745:Methylation; D009707:Nucleosomes / Q000201:enzymology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D006657:Histones; C413655:KDM4C protein, human; D009707:Nucleosomes; D056484:Jumonji Domain-Containing Histone Demethylases
keywords: chromatin regulation; enzyme kinetics; histone demethylase; lysine demethylase 4C (KDM4C); nucleosome; post-translational modification (PTM); substrate specificity