Li Na, Li Yuanyuan, Lv Jie, Zheng Xiangdong, Wen Hong, Shen Hongjie, Zhu Guangjing, Chen Tsai-Yu, Dhar Shilpa S, Kan Pu-Yeh, Wang Zhibin, Shiekhattar Ramin, Shi Xiaobing, Lan Fei, Chen Kaifu, Li Wei, Li Haitao, Lee Min Gyu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
Mol Cell. 2016 Aug 4;63(3):470-84. doi: 10.1016/j.molcel.2016.06.035. Epub 2016 Jul 28.
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.
组蛋白乙酰化，包括乙酰化的H3K14（H3K14ac），通常与基因激活相关。单甲基化的组蛋白H3赖氨酸4（H3K4me1），与其他基因激活标记一起，表示活跃基因。与H3K14ac和H3K4me1通常的基因激活功能相反，我们在此表明双组蛋白修饰标记H3K4me1-H3K14ac被ZMYND8（也称为RACK7）识别，并可起到抑制基因表达的作用。我们将ZMYND8鉴定为H3K4去甲基化酶JARID1D的转录共抑制因子。ZMYND8拮抗转移相关基因的表达，其敲低增加了体外和体内细胞的侵袭性。ZMYND8中的植物同源结构域（PHD）和溴结构域盒介导了ZMYND8对H3K4me1-H3K14ac和H3K4me0-H3K14ac的组合识别。这些发现揭示了标志性的H3K4me1-H3K14ac在减弱基因表达方面的意外作用，并揭示了一种转移抑制性表观遗传机制，其中ZMYND8的PHD-溴结构域盒将H3K4me1-H3K14ac与转移相关基因的下调联系起来。
