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

doi:10.1016/j.molcel.2016.06.035

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. Epub 2016 Jul 28.

Authors

Na Li¹, Yuanyuan Li², Jie Lv³, Xiangdong Zheng², Hong Wen⁴, Hongjie Shen⁵, Guangjing Zhu⁶, Tsai-Yu Chen¹, Shilpa S Dhar¹, Pu-Yeh Kan¹, Zhibin Wang⁶, Ramin Shiekhattar⁷, Xiaobing Shi⁴, Fei Lan⁵, Kaifu Chen³, Wei Li⁸, Haitao Li⁹, Min Gyu Lee¹⁰

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Binding Sites
Cell Line, Tumor
Cell Movement*
Cell Proliferation
DNA Methylation*
Down-Regulation
Gene Expression Regulation, Neoplastic*
Histone Demethylases / genetics
Histone Demethylases / metabolism
Histones / genetics
Histones / metabolism*
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / secondary
Male
Mice, Nude
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / metabolism
Models, Molecular
Neoplasm Invasiveness
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology
Protein Binding
Protein Conformation
Protein Interaction Domains and Motifs
RNA Interference
Receptors for Activated C Kinase
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism*
Time Factors
Transcription, Genetic
Transfection
Tumor Burden
Tumor Suppressor Proteins

Substances

Histones
Minor Histocompatibility Antigens
Receptors for Activated C Kinase
Receptors, Cell Surface
Tumor Suppressor Proteins
ZMYND8 protein, human
Histone Demethylases
KDM5D protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding