2. Academic Validation
  3. ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes

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

  • Mol Cell. 2016 Aug 4;63(3):470-84. doi: 10.1016/j.molcel.2016.06.035.
Na Li 1,  Yuanyuan Li 2,  Jie Lv 3,  Xiangdong Zheng 2,  Hong Wen 4,  Hongjie Shen 5,  Guangjing Zhu 6,  Tsai-Yu Chen 1,  Shilpa S Dhar 1,  Pu-Yeh Kan 1,  Zhibin Wang 6,  Ramin Shiekhattar 7,  Xiaobing Shi 4,  Fei Lan 5,  Kaifu Chen 3,  Wei Li 8,  Haitao Li 9,  Min Gyu Lee 10
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
  • 2 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.
  • 3 Institute for Academic Medicine, The Methodist Hospital Research Institute, Houston, TX 77030, USA; Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, The Methodist Hospital Research Institute, Houston, TX 77030, USA; Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
  • 4 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
  • 5 Key Laboratory of Epigenetics, Institutes of Biomedical Sciences and Key Laboratory of Birth Defect, Children's Hospital, Fudan University, Shanghai 201102, China.
  • 6 Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
  • 7 University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, 1501 NW 10th Avenue, Miami, FL 33136, USA.
  • 8 Division of Biostatistics, Dan L. Duncan Cancer Center, and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: WL1@bcm.edu.
  • 9 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; Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: lht@tsinghua.edu.cn.
  • 10 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA. Electronic address: mglee@mdanderson.org.
PMID: 27477906 DOI: 10.1016/j.molcel.2016.06.035
Abstract

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.

Figures