Abstract
Recognition of histone covalent modifications by 'reader' modules constitutes a major mechanism for epigenetic regulation. A recent upsurge of newly discovered histone lysine acylations, such as crotonylation (Kcr), butyrylation (Kbu), and propionylation (Kpr), greatly expands the coding potential of histone lysine modifications. Here we demonstrate that the histone acetylation-binding double PHD finger (DPF) domains of human MOZ (also known as KAT6A) and DPF2 (also known as BAF45d) accommodate a wide range of histone lysine acylations with the strongest preference for Kcr. Crystal structures of the DPF domain of MOZ in complex with H3K14cr, H3K14bu, and H3K14pr peptides reveal that these non-acetyl acylations are anchored in a hydrophobic 'dead-end' pocket with selectivity for crotonylation arising from intimate encapsulation and an amide-sensing hydrogen bonding network. Immunofluorescence and chromatin immunoprecipitation (ChIP)–quantitative PCR (qPCR) showed that MOZ and H3K14cr colocalize in a DPF-dependent manner. Our studies call attention to a new regulatory mechanism centered on histone crotonylation readout by DPF family members.
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Acknowledgements
We thank Z. Chen for critical comments. We thank the staff members at beamline BL17U of the Shanghai Synchrotron Radiation Facility and S. Fan at Tsinghua Center for Structural Biology for their assistance in data collection, and the China National Center for Protein Sciences Beijing for providing facility support. This work was supported by grants from the Ministry of Science and Technology of China (2016YFA0500700 and 2015CB910503), the National Natural Science Foundation of China (91519304), and the Tsinghua University Initiative Scientific Research Program to H.L. We acknowledge support from The Rockefeller University to C.D.A., and the US National Institute of General Medicine to C.D.A. (GM040922), to Y.Z. (GM105933, DK107868, and GM115961), and to T.P. (GM112365).
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H.L. conceived and designed the study; X.X. designed and performed most of the experiments under the guidance of H.L. Y.L. discovered the crotonyllysine reader activity of DPF domain. T.P. performed the designer nucleosome pulldown assay under the guidance of C.D.A. S.Y., P.Y., S.Z. and Y.L. helped with binding and crystallographic experiments. W.Z., W.X., Y.Z. and C.D.A. provided expertise and critical feedback; H.L. and X.X. wrote the manuscript with input from other authors.
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Xiong, X., Panchenko, T., Yang, S. et al. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat Chem Biol 12, 1111–1118 (2016). https://doi.org/10.1038/nchembio.2218
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DOI: https://doi.org/10.1038/nchembio.2218
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