ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes
Open accessAbstract
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.
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ZMYND8 occupies many active enhancers and recruits KDM5C to super enhancer regions to maintain low H3K4me3 levels resulting in repression of enhancer activity.
“ZMYND8 occupies many active enhancers and recruits KDM5C to super enhancer regions to maintain low H3K4me3 levels resulting in the repression of enhancer activity 35–37.”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [36]
The Results (page unavailable) show that ZMYND8 and JARID1D cooperate to repress metastasis-linked genes: ZMYND8 knockdown reduced JARID1D occupancy and increased H3K4me3 at those genes. The Discussion (page unavailable) suggests ZMYND8 may help recruit JARID1D. These passages do not establish recruitment of KDM5C to super-enhancer regions or repression of enhancer activity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredZMYND8 functions as a reader to recognize the acetylation of histone 3 at K14.
“ZMYND8 (also named PRKCBP1 or RACK7) functions as a reader to recognize the acetylation of histone 3 at K14.”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [36]
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Cites
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- Authors
- Li, N., Li, Y., Lv, J., Zheng, X., Wen, H., Shen, H., Zhu, G., Chen, T.-Y., Dhar, S. S., Kan, P.-Y., Wang, Z., Shiekhattar, R., Shi, X., Lan, F., Chen, K., Li, W., Li, H., & Lee, M. G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Center for Life Sciences (CN)
- Cornell University (US)
- Fudan University (CN)
- Johns Hopkins University (US)
- University of Miami (US)
- Baylor College of Medicine (US)
- Sichuan University (CN)
- Corresponding author
- Li, Wei
- Li, Haitao
- Lee, Min Gyu
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 63
- Issue
- 3
- Pages
- 470-484
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4975651
- OpenAlex
- W2475941856
- Cited by
- 141
- References
- 7
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 13 · 2023: 13 · 2022: 17 · 2021: 26 · 2020: 11 · 2019: 11 · 2018: 13 · 2017: 11 · 2016: 2
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (R01HG007538)
- National Cancer Institute (R01CA157919, P30CA016672, P30CA010815)
- National Institute of General Medical Sciences (R01GM105754, R01GM095659, R01GM078455)
- National Institute of Environmental Health Sciences (R01ES025761)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- ZMYND8, H3K4me1, H3K14ac, histone acetylation, histone methylation, corepressors, H3K4 demethylase, tumor invasion, plant homeodomain, bromodomain, epigenetic silencing
- MeSH terms
- Receptors for Activated C Kinase, Acetylation, Animals, Binding Sites, Cell Movement, Histones, Humans, Lung Neoplasms, Male, Mice, Nude, Models, Molecular, Neoplasm Invasiveness, Prostatic Neoplasms, Protein Binding, Protein Conformation, Receptors, Cell Surface, Time Factors, Transcription, Genetic, Transfection, Down-Regulation, Minor Histocompatibility Antigens, Gene Expression Regulation, Neoplastic, DNA Methylation, Tumor Suppressor Proteins, RNA Interference, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Protein Interaction Domains and Motifs, Histone Demethylases
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