Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 12, Pages 6060-6070Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.696864
Keywords
chromatin regulation; enzyme kinetics; histone demethylase; nucleosome; post-translational modification (PTM); substrate specificity; lysine demethylase 4C (KDM4C)
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Funding
- National Science Foundation Graduate Research Fellowship
- National Institutes of Health (NIH) [R01 CA020535]
- NIH [R01 GM114044]
- University of California San Francisco Nina Ireland Program for Lung Health
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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.
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