Epigenetic regulation in medulloblastoma: from tumor heterogeneity to diagnostic, prognostic, and translational applications.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Epigenetic dysregulation, particularly in Group 3 and Group 4 tumors, is a major driver of tumorigenesis despite relatively few recurrent driver mutations. DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs orchestrate aberrant transcriptional programs governing tumor initiation, progression, and cellular identity. Single-cell and multi-omic studies have revealed epigenetic heterogeneity, cellular plasticity, and microenvironmental interactions underlying therapeutic resistance. Epigenetic alterations provide valuable diagnostic and prognostic biomarkers. DNA methylation profiling is the gold standard for molecular classification, while epigenetic signatures and cerebrospinal fluid circulating tumor DNA support precision diagnosis and disease monitoring. This review integrates recent advances in MB epigenetics into a framework linking cellular plasticity and the tumor microenvironment to biomarker-driven precision therapies. Several comprehensive reviews have summarized the epigenetic landscape of medulloblastoma, focusing primarily on DNA methylation, histone modifications, chromatin remodeling, and subgroup-specific epigenetic alterations. While these studies have substantially advanced our understanding of epigenetic mechanisms, the rapid emergence of single-cell sequencing, spatial transcriptomics, multi-omic integration, and three-dimensional chromatin mapping has reshaped the current view of medulloblastoma biology. These technologies provide unprecedented resolution for dissecting intratumoral heterogeneity, developmental trajectories, and dynamic epigenetic regulation not fully addressed in earlier reviews. In this review, we integrate these recent advances into a unified framework connecting classical epigenetic mechanisms with emerging multidimensional epigenomic technologies. We discuss how these insights facilitate biomarker discovery, improve molecular classification, and accelerate precision epigenetic therapies, highlighting future directions for translational research.