Deciphering epigenetic dysregulation in childhood brain cancer

A growing number of neurodevelopmental disorders and pediatric brain cancers are associated with mutations in histones and chromatin modifiers. Specifically, high-grade glioma (HGG) occurring in children and young adults are defined by histone H3 mutations on two critical residues - lysine 27 to methionine (K27M), and glycine 34 to valine/arginine (G34V/R). H3K27M is a potent dominant negative mutation, resulting in global loss of the repressive H3K27 trimethylation (H3K27me3). Conversely, H3.3G34R/V hinders H3K36 methylation (H3K36me2/3), a mark that acts as a chromatin barrier to H3K27me3. Such global perturbation of the H3K27me/H3K36me axis is strongly implicated as the underlying mechanism of gliomagenesis. Notably, germline haploinsufficiency of H3K27 or H3K36 methyltransferases causes Weaver and Sotos Syndrome, respectively, with shared clinical features of global overgrowth, macrocephaly, and intellectual disability. Using aDrosophilamodel, we show that depletion of either H3K27 or H3K36 methylation results in remarkably similar phenotypic defects and converge on mis-expression of developmental genes and transposable elements. Collectively, this supports the notion that chromatin mutations perturb the epigenome to alter developmental trajectories, and neoplasia occurs from subsequent co-option of oncogenic partners. My future research will study epigenetic reprogramming in mammalian brain development and investigate chromatin-based mechanisms of neurodevelopmental diseases and lethal brain cancer. Dr. Carol Chen is being interviewed for a Scientist position in the Research Institute.