Decoding the regulatory programs governing glioblastoma plasticity.

MYT1L is identified as the dominant safeguard repressor that maintains the neuronal-like low-plasticity state in primary glioblastomas, restricting plasticity even under standard-of-care therapy.

• Why it matters: Glioblastoma progression despite genomic stability under treatment suggests non-genetic plasticity, but it was unclear whether state changes follow predictable regulatory programs.
• What they did: The scDORI deep-learning framework infers enhancer-driven gene-regulatory networks from single-nucleus multiome profiles of more than one million cells, then uses systematic perturbation screens in patient-derived models.
• The result: The inferred hierarchical transition landscape is predictable yet allows cross-lineage trajectories absent from normal neurodevelopment; MYT1L repression suppresses tumor growth and invasion in vivo, while MYT1L loss reactivates plasticity and accelerates malignant features.

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