ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes

Na Li, Yuanyuan Li, Jie Lv, Xiangdong Zheng, Hong Wen, Hongjie Shen, Guangjing Zhu, Tsai Yu Chen, Shilpa S. Dhar, Pu Yeh Kan, Zhibin Wang, Ramin Shiekhattar, Xiaobing Shi, Fei Lan, Kaifu Chen, Wei Li, Haitao Li, Min Gyu Lee

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Histone acetylation, including acetylated H3K14 (H3K14ac), is generally linked to gene activation. Monomethylated histone H3 lysine 4 (H3K4me1), together with other gene-activating marks, denotes active genes. In contrast to usual gene-activating functions of H3K14ac and H3K4me1, we here show that the dual histone modification mark H3K4me1-H3K14ac is recognized by ZMYND8 (also called RACK7) and can function to counteract gene expression. We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D. ZMYND8 antagonized the expression of metastasis-linked genes, and its knockdown increased the cellular invasiveness in vitro and in vivo. The plant homeodomain (PHD) and Bromodomain cassette in ZMYND8 mediated the combinatorial recognition of H3K4me1-H3K14ac and H3K4me0-H3K14ac by ZMYND8. These findings uncover an unexpected role for the signature H3K4me1-H3K14ac in attenuating gene expression and reveal a metastasis-suppressive epigenetic mechanism in which ZMYND8's PHD-Bromo cassette couples H3K4me1-H3K14ac with downregulation of metastasis-linked genes. Li et al. reveal that ZMYND8 recognizes the dual histone mark H3K4me1-H3K14ac and acts as a transcriptional corepressor of the H3K4 demethylase JARID1D. ZMYND8-mediated recognition of H3K4me1-H3K14ac and JARID1D-catalyzed H3K4 demethylation cooperate to antagonize the expression of metastasis-linked genes.

Original languageEnglish (US)
JournalMolecular Cell
Publication statusAccepted/In press - Dec 9 2015


ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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