H3K27M cooperates with ASCL1 to maintain progenitor states and drive gliomagenesis

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.

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Cite

BibTeX RIS

BibTeX

@article{jiao2026h3k27m,
  title = {{H3K27M cooperates with ASCL1 to maintain progenitor states and drive gliomagenesis}},
  author = {Alan L. Jiao and Abolfazl Maghrouni and Arantxa Gutierrez and Alva Annett and Cherubin Manokaran and Tingyu Wen and Niklas Grassl and Jonathan H. Chan and Sylvain Nguyen and Berna Bou-Tayeh and Wajih Jawhar and François Le Dily and Claudia L. Kleinman and Luciano Di Croce and Nada Jabado and Yang Shi},
  journal = {Nature Communications},
  year = {2026},
  month = oct,
  doi = {10.1038/s41467-026-78138-z},
  url = {https://www.nature.com/articles/s41467-026-78138-z},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - H3K27M cooperates with ASCL1 to maintain progenitor states and drive gliomagenesis
AU  - Alan L. Jiao
AU  - Abolfazl Maghrouni
AU  - Arantxa Gutierrez
AU  - Alva Annett
AU  - Cherubin Manokaran
AU  - Tingyu Wen
AU  - Niklas Grassl
AU  - Jonathan H. Chan
AU  - Sylvain Nguyen
AU  - Berna Bou-Tayeh
AU  - Wajih Jawhar
AU  - François Le Dily
AU  - Claudia L. Kleinman
AU  - Luciano Di Croce
AU  - Nada Jabado
AU  - Yang Shi
PY  - 2026
DA  - 2026/10/10
JO  - Nature Communications
DO  - 10.1038/s41467-026-78138-z
UR  - https://www.nature.com/articles/s41467-026-78138-z
AB  - 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.
SN  - 2041-1723
ER  -

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