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.


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


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