Abstract / Summary
Abstract Histone 3 lysine 27-to-methionine substitutions (H3K27M) drive aggressive diffuse midline gliomas by blocking differentiation of radial glial progenitor cells committed to oligodendrogenesis. We establish prolonged differentiation as a powerful tool to uncover regulators of glioma cell states and demonstrate that the pioneer transcription factor (TF) ASCL1 is a key mediator of H3K27M-driven plasticity and tumorigenesis. H3K27M prevents Polycomb silencing of ASCL1 , co-opting this TF to maintain oligodendroglial progenitor states. Consistently, ASCL1 loss drastically impairs tumor formation in vivo. Mechanistically, ASCL1 synergizes with H3K27M to redistribute the chromatin remodeler BRG1 to regulatory elements co-enriched for ASCL1 and SOX motifs, promoting expression of stem and neural progenitor genes at the expense of mesenchymal genes in DMGs. ASCL1 loss acts as a “fire exit”, enabling alternative differentiation despite H3K27M, underscoring the therapeutic potential of targeting stalled differentiation and tumor plasticity in histone-mutant gliomas and cancers with a stem cell hierarchy.