Oncohistone-sculpted epigenetic mechanisms in pediatric brain cancer

Chromatin dynamics, involving reversible changes in chromatin structure, shape key cellular processes and genomic integrity during development and proliferation, with disruptions leading to cancer. Histones, core components of chromatin and substrates for chromatin-modifying enzymes, play crucial roles in oncogenesis when misregulated or mutated. This is particularly pronounced in pediatric hind brain cancers, some of which are driven primarily by the oncohistone H3K27M and the recently identified oncohistone-mimic protein CXorf67/EZHIP. Notably, H3K27M and EZHIP-driven cancers exhibit low mutation burdens, highlighting the enigmatic role of non-mutational epigenetic reprogramming in oncogenesis beyond traditional paradigms of oncogene activation and tumor suppressor loss. Here, we review the impact of H3K27M and EZHIP-driven cancer mechanisms on chromatin and transcriptional dysregulation leading to aberrant cell fate determination, and their potential influence beyond gene activity, affecting broader cellular pathways. Illuminating these mechanisms is crucial for advancing treatment options for pediatric brain cancers, where therapeutic regimens are poorly defined.