Disordered Dna Methylation In Dipg Underlies Phenotypic Plasticity

Abstract Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a dismal prognosis and no effective treatment. Recent studies point to a critical role for epigenetic dysregulation in this disease. Nearly 80% of DIPGs harbor mutations in histone H3 encoding replacement of lysine 27 with methionine (K27M), leading to global loss of the repressive histone H3K27 trimethylation mark, global DNA hypomethylation, and a distinct gene expression profile. However, a static view of the epigenome fails to capture the plasticity of cancer cells and their gene expression states. Recent studies across diverse cancers have highlighted the role of epigenetic variability as a driving force in tumor evolution. Epigenetic variability may underlie the heterogeneity and phenotypic plasticity of DIPG cells and allow for the selection of cellular traits that promote survival and resistance to therapy. We have recently formalized a novel framework for analyzing variability of DNA methylation directly from whole-genome bisulfite sequencing data, allowing computation of DNA methylation entropy at precise genomic locations. Using these methods, we have shown that DIPG exhibits a markedly disordered epigenome, with increased stochasticity of DNA methylation localizing to specific regulatory elements and genes. We evaluate the responsiveness of the DIPG epigenetic landscape to pharmacologic modulation in order to modify proliferation, differentiation state, and immune signaling in DIPG cells.