Su, ZhangliWang, FengbinLee, Jin-HeeStephens, Kimberly E.Papazyan, RomeoVoronina, EkaterinaKrautkramer, Kimberly A.Raman, AnaThorpe, Jeremy J.Boersma, Melissa D.Kuznetsov, Vyacheslav I.Miller, Mitchell D.Taverna, Sean D.Phillips, George N.Jr.Denu, John M.2016-12-012016-12-012016Su, Zhangli, Wang, Fengbin, Lee, Jin-Hee, et al.. "Reader domain specificity and lysine demethylase-4 family function." <i>Nature Communications,</i> 7, (2016) Springer Nature: http://dx.doi.org/10.1038/ncomms13387.https://hdl.handle.net/1911/92734The 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 vitrodemethylation 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.engThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.Journal articlehttp://dx.doi.org/10.1038/ncomms13387