ZMYND11 represses gene expression by binding H3.3K36me3 and preventing transcription elongation.
Major finding: ZMYND11 represses gene expression by binding H3.3K36me3 and preventing transcription elongation.
Concept: Binding of ZMYND11 to H3.3K36me3 abrogates PolII gene occupancy, oncogene expression, and tumor growth.
Impact: ZMYND11 is a variant-specific methylated histone reader that may act to fine-tune gene expression.
Recognition of histone H3 trimethylation (H3K36me3) by histone reader proteins represses transcription elongation in yeast, but the function in mammalian cells is less defined. Wen and colleagues examined the histone binding ability and preference of zinc finger, MYND-type containing 11 (ZMYND11), a transcriptional corepressor and candidate tumor suppressor with several histone binding domains, and made the surprising observation that ZMYND11 is a histone variant-specific methylated histone reader that specifically recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3). A crystal structure of the tandem bromo-PWWP domain of ZMYND11 in complex with H3.3K36me3 revealed that the ZMYND11 PWWP domain formed a conserved aromatic cage around H3.3K36me3 and the bromo-PWWP domains encapsulated serine 31, a H3.3-specific residue indispensable for ZMYND11 binding. In human cells, ZMYND11 colocalized with both histone H3.3 and H3K36me3 specifically within gene bodies in a manner dependent on H3.3K36me3 deposition. ZMYND11 depletion led to an increase in RNA Polymerase II (PolII) occupancy at ZMYND11-enriched loci, implicating ZMYND11 in transcriptional repression through prevention of PolII transcriptional elongation. Consistent with a role for transcriptional regulation in ZMYND11-mediated tumor suppression, the gene expression profile of ZMYND11-depleted cells was enriched for cancer-associated genes, and ZMYND11 overexpression in cancer cell lines suppressed tumor cell growth in vitro and in vivo whereas overexpression of ZMYND11 mutants with reduced binding to H3.3K36me3 binding (one of which has been identified in patients with colorectal cancer) did not. Of note, reduced ZMYND11 expression was observed in several human cancers, and low ZMYND11 expression in patients with breast cancer was correlated with shorter disease-free survival. ZMYND11 also showed reduced binding to K36me3 peptides in the presence of H3.3 G34 mutations found in pediatric glioblastoma. Taken together, these findings implicate ZMYND11 as a histone variant-specific reader protein and suggest that its tumor suppressor activity may be attributable to modulation of transcription elongation.