ZMYND8 acts as a transcriptional corepressor of JARID1D to suppress cellular invasion.
Major finding: ZMYND8 acts as a transcriptional corepressor of JARID1D to suppress cellular invasion.
Mechanism: The PHD and Bromo domains of ZMYND8 recognize the dual histone mark H3K4me1-H3K14ac.
Impact: H3K4me1-H3K14ac has an unexpected role in transcriptional repression of metastasis genes.
Histone modifications play key roles in the regulation of gene expression. Monomethylation of histone 3 lysine 4 (H3K4me1) and acetylation of H3K14 (H3K14ac) are generally associated with active genes. These marks can be modified by a number of enzymes, including the male-specific H3K4 demethylase JARID1D expressed on the Y chromosome that is a transcriptional corepressor involved in suppressing prostate cancer metastasis. Li, Li, Lv, and colleagues investigated the role of JARID1D in gene regulation and identified zinc finger MYND-type containing 8 (ZMYND8) as a JARID1D-associated protein. ZMYND8 has putative chromatin-binding modules, including a PHD and Bromo domain, suggesting a possible role for ZMYND8 in JARID1D-mediated gene repression. Like JARID1D, ZMYND8 suppressed prostate cancer cell invasion both in vitro and in vivo, and RNA sequencing revealed that JARID1D depletion and ZMYND8 depletion resulted in the upregulation of highly overlapping sets of genes, including genes linked to metastatic processes. There was a high level of overlap between ZMYND8 and JARID1D chromatin-bound regions, and ZMYND8 and JARID1D co-occupied and co-downregulated a number of metastasis-associated genes, including SLUG, CD44, VEGFA, EGFR, MMP1, and MMP3. ZMYND8 was involved in maintaining JARID1D occupancy, and ZMYND8 knockdown reduced JARID1D occupancy and increased H3K4me3, suggesting that ZMYND8 acts as a transcriptional corepressor of JARID1D. The PHD and Bromo domains of ZMYND8 bound to the dual histone modifications H3K4me1-H3K14ac and H3K4me0-H3K14ac. JARID1D colocalized with ZMYND8 at the transcription start sites of metastasis-associated genes marked by H3K4me1-H3K14ac, resulting in their transcriptional repression. In addition to identifying a role for ZMYND8 as a JARID1D transcriptional corepressor of metastasis-linked genes, these findings link the H3K4me1-H3K14ac histone signature with transcriptional repression.