Abstract
We report the identification of a new type of histone mark, lysine 2-hydroxyisobutyrylation (Khib), and identify the mark at 63 human and mouse histone Khib sites, including 27 unique lysine sites that are not known to be modified by lysine acetylation (Kac) and lysine crotonylation (Kcr). This histone mark was initially identified by MS and then validated by chemical and biochemical methods. Histone Khib shows distinct genomic distributions from histone Kac or histone Kcr during male germ cell differentiation. Using chromatin immunoprecipitation sequencing, gene expression analysis and immunodetection, we show that in male germ cells, H4K8hib is associated with active gene transcription in meiotic and post-meiotic cells. In addition, H4K8ac-associated genes are included in and constitute only a subfraction of H4K8hib-labeled genes. The histone Khib mark is conserved and widely distributed, has high stoichiometry and induces a large structural change. These findings suggest its critical role on the regulation of chromatin functions.
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Acknowledgements
S.K.'s group research is supported by Agence Nationale de la Recherche EpiSperm and Institut National du Cancer funds. E.M. was supported by a three-year grant from the French Ministry of Research and an Association pour la Recherche sur le Cancer fellowship for her fourth-year PhD.
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Y.Z. and S.K. designed the experiments and wrote the paper. L.D. designed the experiments; synthesized chemicals; performed western blotting, immunoprecipitation, MS quantification and analysis; wrote the paper; and participated in other experiments. C.P. performed in vitro enzymatic assays. Y.C. and Z.D. performed MS analysis. E.M., Z.L., A.D., T.B., S.R., F.J., H.I. and B.R. performed immunofluorescence experiments, IHC and ChIP-Seq. B.R.S. and C.D.A. performed the Tetrahymena experiments.
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Y.Z. is a shareholder and a member of the scientific advisory board of PTM BioLabs, Co., Ltd. (Chicago, IL).
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Supplementary Results, Supplementary Figures 1–9, Supplementary Tables 1–5 and Supplementary Note. (PDF 3783 kb)
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Dai, L., Peng, C., Montellier, E. et al. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat Chem Biol 10, 365–370 (2014). https://doi.org/10.1038/nchembio.1497
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DOI: https://doi.org/10.1038/nchembio.1497
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