title: ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes.
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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Lv
authors.affiliation: 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.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wen
authors.affiliation: Key Laboratory of Epigenetics, Institutes of Biomedical Sciences and Key Laboratory of Birth Defect, Children's Hospital, Fudan University, Shanghai 201102, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Guangjing
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Dhar
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Pu-Yeh
authors.initials: PY
authors.lastname: Kan
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ramin
authors.initials: R
authors.lastname: Shiekhattar
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Shi
authors.affiliation: Key Laboratory of Epigenetics, Institutes of Biomedical Sciences and Key Laboratory of Birth Defect, Children's Hospital, Fudan University, Shanghai 201102, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.affiliation: 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.
authors.forename: Kaifu
authors.initials: K
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins
chemical_list: D006657:Histones; D015778:Minor Histocompatibility Antigens; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C000617312:ZMYND8 protein, human; D056466:Histone Demethylases; C095561:KDM5D protein, human