GSE99979 Recognition of a pediatric glioblastoma-associated histone mutation by chromatin reader ZMYND8 promotes tumorigenesis

Contributors : Rui Guo ; Yang ShiSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Mus musculusHistone H3 point mutations have recently been identified in pediatric brain cancers, including missense mutations on histone H3 at positions 27 (lysine to methionine; K27M) and 34 (glycine to arginine, G34R), respectively. H3K27M mutations are associated with a majority of pediatric Diffuse Intrinsic Pontine Pediatric Glioma (DIPG) cases, while H3.3G34R is found in pediatric glioblastoma (GBM) arising in the cerebral cortex1,2. While the mechanisms of H3K27M-driven tumorigenesis are beginning to unravel, much less is known about the H3.3G34R mutation. Here, we provide both biochemical and structural evidence that the PHD (plant homedomain) domain of the enhancer-binding protein, RACK7 (ZMYND8), recognizes H3.3G34R mutant histone via a mechanism distinct from other PHD domains. In an H3.3G34R-expressing neuronal precursor cell line, we demonstrate that RACK7 is aberrantly recruited to enhancers bound by H3.3G34R, resulting in the down-regulation of many neuronal genes, and the up-regulation of oncogenes such as MYC. Neural precursor cells expressing H3.3G34R showed enhanced tumor growth when injected subcutaneously. Inhibiting RACK7 binding to H3.3G34R reduces tumor size and alters gene expression, suggesting that H3.3G34R regulation of enhancers via RACK7 promotes tumorigenesis. Specifically, we show that both the gene expression and tumor si...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Mus musculus Source Type: research