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BAF complex maintains glioma stem cells in pediatric H3K27M-glioma [scRNA-seq]

ABSTRACT: Diffuse midline gliomas (DMGs) are uniformly fatal pediatric central nervous system cancers, refractory to standard of care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3.3 and H3.1, K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape, which we interrogated here for epigenetic dependencies using a CRISPR screen in patient-derived H3K27M-glioma neurospheres. We show that H3K27M-glioma cells are dependent on core components of the mammalian SWI/SNF (BAF) chromatin remodeling complex for maintaining glioma stem cells in a cycling, oligodendrocyte precursor cell (OPC)-like state. Genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacological suppression opposes proliferation, promotes differentiation, and improves overall survival of patient-derived xenograft (PDX) models. In summary, we demonstrate that therapeutic inhibition of BAF complex has translational potential for children with H3K27M-gliomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212782 | GEO | 2022/09/15

REPOSITORIES: GEO

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BAF complex maintains glioma stem cells in pediatric H3K27M-glioma [RNA-seq]

Project description:Diffuse midline gliomas (DMGs) are uniformly fatal pediatric central nervous system cancers, refractory to standard of care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3.3 and H3.1, K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape, which we interrogated here for epigenetic dependencies using a CRISPR screen in patient-derived H3K27M-glioma neurospheres. We show that H3K27M-glioma cells are dependent on core components of the mammalian SWI/SNF (BAF) chromatin remodeling complex for maintaining glioma stem cells in a cycling, oligodendrocyte precursor cell (OPC)-like state. Genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacological suppression opposes proliferation, promotes differentiation, and improves overall survival of patient-derived xenograft (PDX) models. In summary, we demonstrate that therapeutic inhibition of BAF complex has translational potential for children with H3K27M-gliomas.

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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.

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