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Decoding Plasticity Regulators and Transition Trajectories in Glioblastoma with Single-cell Multiomics [scRNA-Seq]

ABSTRACT: Glioblastoma (GB) is incurable and resistant to therapy despite genomic stability under treatment, implicating non-genetic cellular plasticity as a central driver of progression. Whether such plasticity reflects stochastic state switching or is governed by predictable gene regulation has remained unresolved. We applied scDORI, a deep-learning framework that infers enhancer-driven gene regulatory networks at single cell resolution, to single-nucleus multi-ome profiles of over one million cells from primary GBs. Integrating computational inference with systematic gain-of-function screens across patient-derived models, we show that GB cellular plasticity is governed by a structured regulatory program with an asymmetric interplay of activators and repressors. The resulting transition landscape is hierarchical and predictable, yet permits cross-lineage trajectories absent from normal neurodevelopment. Within this landscape, low-plasticity states such as the Neuronal-like state are not stable differentiation endpoints but actively maintained configurations, stabilized by a network of safeguard repressors that silence alternate fates. MYT1L emerged as the dominant member of this network, binding and repressing master regulators of every alternative state to consolidate Neuronal-like identity. MYT1L restricted plasticity even under standard-of-care therapy and suppressed tumor growth and invasion in vivo. Conversely, MYT1L loss reactivated plasticity and accelerated malignant features, demonstrating that low-plasticity identity requires continuous repression. These findings reframe malignant cell state stability as a balance between activation and continuous repression, and nominate safeguard repressors as candidate therapeutic targets distinct from differentiation-inducing activators, with potential relevance across cancers in which phenotypic switching drives therapy resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE339482 | GEO | 2026/08/24

REPOSITORIES: GEO

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Project description:Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs but not the neuronal program during reprogramming and neurogenesis and in primary mouse neurons. The repressive function of Myt1l is mediated by recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knock-down of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar ‘many-but-one’ lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.

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Decoding Plasticity Regulators and Transition Trajectories in Glioblastoma with Single-cell Multiomics [scRNA-Seq]

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