Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [CUTAC]

ABSTRACT: Phenotypic plasticity, a hallmark of cancer facilitated by epigenomic reprogramming, represents a significant challenge but also therapeutic opportunity for cancer treatment. How plasticity is regulated in diffuse midline gliomas (DMGs), incurable pediatric brain tumors characterized by oncogenic H3K27M histone mutations, is not understood. Here we demonstrate that H3K27M-driven plasticity requires the lineage-specific, pioneer transcription factor (TF) ASCL1. Prolonged differentiation reveals clinically relevant plasticity in DMGs, which segregate into ASCL1-high, neural progenitor cell (NPC)-like gliomaspheres and ASCL1-low, mesenchymal (MES)-like adherent subpopulations. Direct transcriptional activation by ASCL1 enables super enhancers to sustain NPC programs de-repressed by H3K27M. H3K27M loss induces an irreversible MES-like state, suppresses plasticity by abolishing the ASCL1-high state, and is largely phenocopied by loss of ASCL1. Knocking out ASCL1 in DMG lines robustly inhibited tumor growth and significantly extended survival of recipient mice. Our results suggest targeting epigenetic plasticity to suppress master TF-driven progenitor states as a general therapeutic opportunity in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269554 | GEO | 2026/07/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [RNA-seq]

Project description:Phenotypic plasticity, a hallmark of cancer facilitated by epigenomic reprogramming, represents a significant challenge but also therapeutic opportunity for cancer treatment. How plasticity is regulated in diffuse midline gliomas (DMGs), incurable pediatric brain tumors characterized by oncogenic H3K27M histone mutations, is not understood. Here we demonstrate that H3K27M-driven plasticity requires the lineage-specific, pioneer transcription factor (TF) ASCL1. Prolonged differentiation reveals clinically relevant plasticity in DMGs, which segregate into ASCL1-high, neural progenitor cell (NPC)-like gliomaspheres and ASCL1-low, mesenchymal (MES)-like adherent subpopulations. Direct transcriptional activation by ASCL1 enables super enhancers to sustain NPC programs de-repressed by H3K27M. H3K27M loss induces an irreversible MES-like state, suppresses plasticity by abolishing the ASCL1-high state, and is largely phenocopied by loss of ASCL1. Knocking out ASCL1 in DMG lines robustly inhibited tumor growth and significantly extended survival of recipient mice. Our results suggest targeting epigenetic plasticity to suppress master TF-driven progenitor states as a general therapeutic opportunity in cancer.

2026-07-10 | GSE269557 | GEO

Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [CUT&TAG]

2026-07-10 | GSE269556 | GEO

Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [CUT&RUN]

2026-07-10 | GSE269555 | GEO

An E2 ubiquitin conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function

Project description:The H3K27M oncogenic histone (oncohistone) mutation drives ~80% of incurable childhood brain tumors known as diffuse midline gliomas (DMGs). The major molecular feature of H3K27M mutant DMGs is a global loss of H3K27 tri-methylation (H3K27me3), a phenotype conserved in Caenorhabditis elegans (C. elegans). Here we perform unbiased genome-wide suppressor screens in C. elegans expressing H3K27M, and isolate 20 suppressors, all of which at least partially restore H3K27me3. 19/20 suppressor mutations map to the same histone H3.3 gene in which the K27M mutation was originally introduced. Most of these create single amino acid substitutions between residues R26-Y54, which do not disrupt oncohistone expression. Rather, they are predicted to impair interactions with the Polycomb Repressive Complex 2 (PRC2) and are functionally conserved in human cells. Further, we mapped a single extragenic H3K27M suppressor to ubc-20, an E2 ubiquitin conjugating enzyme, whose loss rescued H3K27me3 to nearly 50% wild-type levels despite continued oncohistone expression and chromatin incorporation. We demonstrate that ubc-20 is the major enzyme responsible for generating di-ubiquitinated histone H2B. Our study provides in vivo support for existing models of PRC2 inhibition via direct oncohistone contact, and suggests that the effects of H3K27M may be modulated by H2B ubiquitination.

2024-11-20 | GSE275118 | GEO

ASCL1: a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.

2023-12-08 | PXD037670 | Pride

Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution

Project description:Single-cell sequencing has revealed cell state heterogeneity across diverse healthy and malignant tissues. However, the extent these cell states are plastic or heritable remains largely unknown. To address this, we introduce PATH (Phylogenetic Analysis of Trait Heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Here, we used PATH to measure phylogenetic correlations on single-cell phylogenies derived from gliomaspheres to reveal the somatic evolutionary relationships between Neural Progenitor-like (NPC), Oligodendrocyte Progenitor-like (OPC), Astrocyte-like (AC), and Mesenchymal-like (MES) cancer cell states.

2024-08-12 | GSE273357 | GEO

Cell-of-origin and Developmental Trajectories Cooperate to Determine Chromatin Landscapes in Histone-Mutant Diffuse Midline Gliomas

Project description:Diffuse midline gliomas (DMGs) are universally fatal pediatric brain tumors associated with mutations in genes encoding either histone H3.1 or histone 3.3, often substitution of methionine for lysine 27 (H3K27M). H3K27 is a critical determinant of chromatin state via methylation by Enhancer-of-Zeste-Homolog-2 (EZH2). Previous reports have suggested that the pathologically low levels of H3K27me3 found in histone-mutant DMGs result primarily from H3K27M inhibiting EZH2 directly, but recent reports have called this model into question. To better understand the chromatin landscape of DMGs, we applied CUT&RUN to patient-derived DMG cell lines. Remarkably, we find that the PRC2 activity is similar in DMGs and embryonic stem cells, suggesting a primitive cell-of-origin, despite transcriptionally active regions maintaining markers of both stem cells and differentiated cells. We also show that exogenous expression of H3.3M at physiological levels has little effect on H3K27me3 levels, that H3K27M can colocalize with H3K27me3 in vivo and that the H3.3K27M oncohistone does not show evidence of sequestering PRC2 components. Our results suggest that chromatin landscapes in DMGs are a consequence of a stem-like chromatin state that is retained despite activation of differentiation programs. Our findings have implications for understanding DMG gliomagenesis and therapeutic approaches centered on epigenome-modifying agents.

2020-09-08 | GSE118099 | GEO

Transcription factor expression levels and environmental signals constrain transcription factor innovation

Project description:TF expression constrains opportunity for innovation

| PRJEB64150 | ENA

Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [CUTAC]

Project description:Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [CUTAC]

| PRJNA1122513 | ENA

Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [CUT&TAG]

Project description:Targeting the oncohistone-ASCL1 axis disrupts plasticity and suppresses pediatric gliomas [CUT&TAG]

| PRJNA1122514 | ENA