Understanding The Epigenetic Landscape and Cellular Architecture of Childhood Brain Tumors

Abstract The development of the brain is an intricately ordered process that requires the differentiation of generalized progenitor cells into a bevy of specialized mature cell types. Recent evidence has demonstrated that shifts in epigenetic markers, such as DNA methylation and histone post-translational modification, underpin the exquisitely well-orchestrated changes in cellular activity observed during brain development. Similarly, in the setting of pediatric brain cancer, aberrations in the epigenomic landscape are being increasingly appreciated as fundamental to the process of oncogenesis. These aberrations seem to underpin a more general phenomenon ofdevelopmental “stalling,” which has emerged a s an important hallmark of these tumors and given new perspective on these historically poorly understood cancers. In this article, we will review recent advances in our understanding of epigenetic dysregulation in childhood brain tumors and how this knowledge is being applied towards improving patient care. In particular, we highlight the discovery of tumor-specific epigenetic “signatures” and their utility as both diagnostic and prognostic tools in the clinic, as well as the identification and study of oncogenic mutations in epigenetic regulators in these tumors. We will also discuss how single-cell approaches have uncovered an astonishing complexity and fluidity in the gene expression programs that underpin childhood brain tumor cell behavior and how these programs might be relevant for clinical practice. Lastly, we will explore how these findings are being applied both to inform further studies of childhood brain tumor biology and to design novel molecular therapeutic approaches.