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Histone H3.3G34-mutant interneuron progenitors co-opt PDGFRA for gliomagenesis

ABSTRACT: Histone H3.3 glycine 34 to arginine/valine (H3.3G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These tumors show exquisite regional and temporal specificity, suggesting a developmental context permissive to the effects of G34R/V mutations. Here we present the molecular landscape of G34R/V gliomas (n = 83) and show that ~50% bear activating mutations in PDGFRA, with strong selection pressure for PDGFRAMUT clones at recurrence. We show that G34R/V tumors arise in interneuron progenitors of the foetal ventral forebrain, expressing GSX2 and the DLX family of homeobox transcription factors, where terminal neuronal differentiation is impaired through aberrant G34R/V-mediated H3K27me3. Frequent co-occurrence of G34R/V & PDGFRAMUT is facilitated in this interneuron lineage-of-origin as PDGFRA forms an aberrant chromatin loop with the adjacent GSX2, hijacking its active chromatin conformation. At the single-cell level, G34R/V tumors entirely lack oligodendroglial transcriptional programs prominent in other glioma entities, and instead harbour dual neuronal and astroglial compartments. CRISPR-removal of H3.3G34R/V does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRAMUT are potently oncogenic regardless of G34 mutation. Collectively, our results suggest that G34R/V gliomas arise in foetal interneuron progenitors unable to terminally differentiate, enabling co-option of PDGFRA through inappropriate expression and activating mutations to promote gliogenesis and oncogenicity. Reliance on PDGFRA for oncogenesis may be of therapeutic opportunity in G34R/V glioma.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE146731 | GEO | 2020/11/30

REPOSITORIES: GEO

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H3.3G34R/V-transformed interneuron progenitors co-opt PDGFRA for gliomagenesis

Project description:Histone H3.3 glycine 34 to arginine/valine (H3.3G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These tumors show exquisite regional and temporal specificity, suggesting a developmental context permissive to the effects of G34R/V mutations. Here we present the molecular landscape of G34R/V gliomas (n=85) and show that 50% bear activating mutations in PDGFRA, with strong selection pressure for PDGFRAMUT clones at recurrence. We show that G34R/V tumors arise in interneuron progenitors of the foetal ventral forebrain expressing GSX2 and the DLX family of homeobox transcription factors, where terminal neuronal differentiation is impaired through aberrant G34R/V-mediated H3K27me3. Frequent co-occurrence of G34R/V & PDGFRAMUT is facilitated in this interneuron lineage-of-origin as PDGFRA forms an aberrant chromatin loop with the adjacent GSX2, hijacking its active chromatin conformation. At the single-cell level, G34R/V tumours entirely lack oligodendroglial transcriptional programs prominent in other glioma entities, and instead harbour dual neuronal and astroglial compartments. CRISPR-removal of H3.3G34R/V does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRAMUT are potently oncogenic regardless of G34 mutation. Collectively, our results suggest that G34R/V gliomas arise in foetal interneuron progenitors unable to undergo terminal differentiation, enabling co-option of PDGFRA through inappropriate expression and activating mutations to promote gliogenesis and oncogenicity. Reliance on PDGFRA for oncogenesis may be of therapeutic opportunity in G34R/V glioma.

| EGAS00001004301 | EGA

Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants [ChIP-Seq]

Project description:Point mutations within the histone H3.3 are frequent in aggressive childhood brain tumours known as paediatric high-grade gliomas (pHGGs). Intriguingly, different mutations arise in discrete anatomical regions: H3.3-G34R within the forebrain and H3.3-K27M preferentially within the hindbrain. The reasons for this contrasting aetiology are unknown. By engineering human foetal neural stem cell cultures from distinct regions, we demonstrate here that cell-intrinsic regional identity provides differential responsiveness to each mutant that mirrors the origins of pHGGs. Focusing on H3.3-G34R, we find that the oncohistone supports proliferation of forebrain cells, while inducing a cytostatic response in the hindbrain. Mechanistically, H3.3-G34R does not impose widespread transcriptional or epigenetic changes, but impairs recruitment of ZMYND11, a transcriptional repressor of highly expressed genes. We therefore propose that H3.3-G34R promotes tumorigenesis by stabilising the expression of key progenitor genes and, thus, locking initiating forebrain cells into their preexisting immature state.

2021-03-24 | GSE163185 | GEO

Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants [RNA-Seq]

2021-03-24 | GSE163044 | GEO

Human ESC-based modeling of H3.3G34R-mutant high grade glioma

Project description:H3.3G34R-mutant gliomas are lethal tumors of the cerebral hemispheres, with unknown mechanisms of topographic specificity and tumorigenicity. We developed a human embryonic stem cell (hESC)-based model of H3.3G34R-mutant glioma that recapitulates the anatomical and genetic characteristics of the patient tumors.

2021-02-25 | GSE147543 | GEO

Recognition of a pediatric glioblastoma-associated histone mutation by chromatin reader ZMYND8 promotes tumorigenesis

Project description:Histone H3 point mutations have recently been identified in pediatric brain cancers, including missense mutations on histone H3 at positions 27 (lysine to methionine; K27M) and 34 (glycine to arginine, G34R), respectively. H3K27M mutations are associated with a majority of pediatric Diffuse Intrinsic Pontine Pediatric Glioma (DIPG) cases, while H3.3G34R is found in pediatric glioblastoma (GBM) arising in the cerebral cortex1,2. While the mechanisms of H3K27M-driven tumorigenesis are beginning to unravel, much less is known about the H3.3G34R mutation. Here, we provide both biochemical and structural evidence that the PHD (plant homedomain) domain of the enhancer-binding protein, RACK7 (ZMYND8), recognizes H3.3G34R mutant histone via a mechanism distinct from other PHD domains. In an H3.3G34R-expressing neuronal precursor cell line, we demonstrate that RACK7 is aberrantly recruited to enhancers bound by H3.3G34R, resulting in the down-regulation of many neuronal genes, and the up-regulation of oncogenes such as MYC. Neural precursor cells expressing H3.3G34R showed enhanced tumor growth when injected subcutaneously. Inhibiting RACK7 binding to H3.3G34R reduces tumor size and alters gene expression, suggesting that H3.3G34R regulation of enhancers via RACK7 promotes tumorigenesis. Specifically, we show that both the gene expression and tumor size regulation are critically dependent on the physical interaction of H3.3G34R with RACK7. Both regulations are compromised in the absence of RACK7, and can be rescued by wildtype, but not an H3.3G34R-binding defective, RACK7. Taken together, we have identified a reader for H3.3G34R and demonstrate that RACK7 binding to H3.3G34R alters enhancer activity to directly suppress neural gene transcription and to increase oncogenic propensity of neural precursor cells, thus providing a potential molecular basis for pediatric GBM driven by the H3.3G34R mutation.

2024-04-14 | GSE99979 | GEO

Histone H3-G34V and H3-G34R mutant fission yeast exhibit distinct chromatin changes and different DNA damage sensitivities.

Project description:Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R mutant histone H3.3. H3.3-G34R mutants are common in tumors additionally mutant for p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, but minimally affects transcriptional control. H3-G34R mutants exhibit genomic instability and increased replicative stress including slowed replication fork restart although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and on damage have altered HR protein dynamics suggestive that H3-G34R slows resolution of HR-mediated repair. In summary our analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

2018-11-15 | GSE106979 | GEO

Histone H3G34R mutation causes replicative stress, defective homologous recombination and genomic instability in Fission Yeast

2017-07-20 | GSE96842 | GEO

Insulator dysfunction and oncogene activation in IDH mutant gliomas

Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models. ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.

2015-12-23 | E-GEOD-70991 | biostudies-arrayexpress

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [RNA-seq]

Project description:The recurrent mutation of histone variant H3.3 at glycine-34 (H3.3G34) defines a type of pediatric glioma. Characteristic changes to the epigenome associated with the disease are thought to be the consequence of altered methylation of the adjacent lysine-36 (K36) residue, but the complexity of this regulatory pathway in humans, combined with a multi-component disease etiology, has limited our understanding of how H3.3G34 mutations contribute to oncogenesis. Here we use Neurospora crassa to show that the most common mutation associated with this tumor, glycine to arginine (G34R), drives aberrant heterochromatin formation and abnormal growth by inhibiting the H3K36 methyltransferase ASH1. Inactivation of ASH1, either directly or with H3G34R, drives spurious intergenic DNA methylation, redistribution of H3K27 methylation, and derepression of silent genes. We provide evidence that these defects are largely due to aberrant activity of RNA polymerase II (RNAPII)-associated SET-2, and propose targeted SET-2 inhibition as a therapeutic strategy for H3.3G34R gliomas.

2022-10-19 | GSE134451 | GEO

The histone H3G34R mutation disrupts the epigenome via catalytic inactivation of the ASH1 H3K36 methyltransferase [ChIP-seq]

2022-10-19 | GSE134449 | GEO

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