Epigenetic dysregulation of high-grade gliomas: from heterogeneity to brain network modulation

High-grade gliomas (HGGs), including glioblastoma and diffuse midline glioma, highlight one of the most aggressive brain tumors in adults and children with dismal prognosis despite intensive treatment regimens. Recently, epigenetic dysregulation has emerged as a fundamental hallmark of HGG biology, and the epigenetic alterations contribute not only to the molecular classification of HGGs but also to their malignant functional biology. Another notable feature of epigenetic dysregulation in HGGs is its influence on intratumoral heterogeneity, via possible modification of the neuron-glioma network in the brain. In this review, we aim to compile recent advances in our understanding of epigenetic dysregulation in HGGs, focusing on key mechanisms such as DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs. Furthermore, we will update our knowledge on the unexpected biology of glioma interaction with neuronal components from a standpoint of epigenetic heterogeneity. By discussing the epigenetic landscape of HGGs, we aim to provide a framework for future research and therapeutic innovation in the management of these devastating tumors.