Reader domain specificity and lysine demethylase-4 family function

Zhangli Su, Fengbin Wang, Jin-Hee Lee, Kimberly E. Stephens, Romeo Papazyan, Ekaterina Voronina, Kimberly A. Krautkramer, Ana Raman, Jeremy J. Thorpe, Melissa D. Boersma, Vyacheslav I. Kuznetsov, Mitchell D. Miller, Sean D. Taverna (), George N. Phillips () and John M. Denu ()
Additional contact information
Zhangli Su: Wisconsin Institute for Discovery, Morgridge Institute for Research, University of Wisconsin–Madison
Fengbin Wang: Biosciences at Rice, Rice University
Jin-Hee Lee: Wisconsin Institute for Discovery, Morgridge Institute for Research, University of Wisconsin–Madison
Kimberly E. Stephens: The Johns Hopkins University School of Medicine
Romeo Papazyan: The Johns Hopkins University School of Medicine
Ekaterina Voronina: University of Montana
Kimberly A. Krautkramer: Wisconsin Institute for Discovery, Morgridge Institute for Research, University of Wisconsin–Madison
Ana Raman: The Johns Hopkins University School of Medicine
Jeremy J. Thorpe: The Johns Hopkins University School of Medicine
Melissa D. Boersma: Wisconsin Institute for Discovery, Morgridge Institute for Research, University of Wisconsin–Madison
Vyacheslav I. Kuznetsov: Wisconsin Institute for Discovery, Morgridge Institute for Research, University of Wisconsin–Madison
Mitchell D. Miller: Biosciences at Rice, Rice University
Sean D. Taverna: The Johns Hopkins University School of Medicine
George N. Phillips: Biosciences at Rice, Rice University
John M. Denu: Wisconsin Institute for Discovery, Morgridge Institute for Research, University of Wisconsin–Madison

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract The KDM4 histone demethylases are conserved epigenetic regulators linked to development, spermatogenesis and tumorigenesis. However, how the KDM4 family targets specific chromatin regions is largely unknown. Here, an extensive histone peptide microarray analysis uncovers trimethyl-lysine histone-binding preferences among the closely related KDM4 double tudor domains (DTDs). KDM4A/B DTDs bind strongly to H3K23me3, a poorly understood histone modification recently shown to be enriched in meiotic chromatin of ciliates and nematodes. The 2.28 Å co-crystal structure of KDM4A-DTD in complex with H3K23me3 peptide reveals key intermolecular interactions for H3K23me3 recognition. Furthermore, analysis of the 2.56 Å KDM4B-DTD crystal structure pinpoints the underlying residues required for exclusive H3K23me3 specificity, an interaction supported by in vivo co-localization of KDM4B and H3K23me3 at heterochromatin in mammalian meiotic and newly postmeiotic spermatocytes. In vitro demethylation assays suggest H3K23me3 binding by KDM4B stimulates H3K36 demethylation. Together, these results provide a possible mechanism whereby H3K23me3-binding by KDM4B directs localized H3K36 demethylation during meiosis and spermatogenesis.

Date: 2016
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DOI: 10.1038/ncomms13387

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