Epigenetic Dysregulation Promotes Gene Activation in Pediatric Glioma

Recurrent heterozygous mutations in histone variant genes, including H3F3A, which encodes histone variant H3.3, frequently occur in pediatric high-grade gliomas (pHGG). Recent studies suggest that Lys27M (K27M) mutation of H3.3 is associated with global reduction of the repressive histone mark H3K27 trimethylation (H3K27me3), suggesting that mutation-driven epigenetic changes may regulate gene expression in these tumors. Bender and colleagues confirm that pHGGs expressing K27M-mutant H3.3 but not other H3.3 mutations exhibit a specific reduction in H3K27 posttranslational modification and reduced H3K27me3 occupancy across the genome. K27M-mutant H3.3 functioned as a dominant negative to inhibit H3K27 di- and trimethylation of wild-type H3 histones locally and globally. This effect was mediated by increased interaction of K27M-mutant H3.3 with Polycomb repressive complex 2 (PRC2) and suppression of the PRC2 component enhancer of zeste 2 (EZH2), an H3K27-specific histone methyltransferase. Of note, genes differentially regulated in K27M-mutant pHGGs were enriched for PRC2 target genes known to be modified at H3K27; reduced H3K27me3 occupancy was detected in 66% of transcriptionally activated genes, including genes that contribute to gliomagenesis, whereas focally increased H3K27me3 levels were associated with decreased expression of a subset of genes. In addition, K27M-mutant pHGGs exhibited an altered DNA methylation profile compared with H3.3–wild-type tumors characterized by global DNA hypomethylation, in particular surrounding the transcriptional start sites of upregulated genes. Intriguingly, concomitant H3K27me3 loss and promoter hypomethylation occurred in 30% of these genes, and 74% of upregulated genes harbored one or both of these epigenetic changes. Although additional studies are needed to understand the targeted regulation of these modifications at specific genetic loci, these results support a dynamic relationship between H3K27me3 and DNA methylation and identify complex epigenetic dysregulation as a critical mechanism underlying establishment of the gene expression profile in pHGG tumors.

Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 2013 Oct 31 [Epub ahead of print].