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Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [ChIP-Seq]

ABSTRACT: Diffuse midline glioma (DMG) is an incurable tumor arising in brainstem and midline structures. Most DMGs harbor missense histone H3 mutations replacing lysine 27 with methionine (H3 K27M). The mechanisms underlying regional selectivity for H3 K27M mutations, which are found almost exclusively in DMG, are not well understood. Here, we use a conditional knock-in mouse model to probe the postnatal brain region-specific oncogenic effects of H3.3 K27M in embryonic GFAP+ neural stem cells. We show that H3.3 K27M reduces oligodendrocyte differentiation in a region-specific manner and increases postnatal proliferation of distinct progenitor states by brain region in vivo, selectively expanding the oligodendrocyte-lineage in the ventral pons. Cellular morphology, marker expression, and transcriptomic analyses of primary region-specific mouse OPC cultures demonstrated cell-intrinsic differences in wild-type brainstem and forebrain OPC differentiation dynamics. H3.3 K27M drives cell-autonomous increase in brainstem-derived OPC proliferation and disrupts intrinsic region-specific transcriptional programs, delaying differentiation in forebrain-derived OPCs and restraining full maturation of brainstem-derived OPCs. H3.3 K27M-mediated changes include brainstem-selective upregulation of genes in Bmp, Wnt, and Notch pathways that are relevant in DMG pathogenesis. Our findings reveal that H3.3 K27M differentially disrupts cell-autonomous regional oligodendrocyte development, which may provide an opportunistic window for brainstem-selective gliomagenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE310474 | GEO | 2026/05/22

REPOSITORIES: GEO

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Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [scRNA-seq]

Project description:Diffuse midline glioma (DMG) is an incurable tumor arising in brainstem and midline structures. Most DMGs harbor missense histone H3 mutations replacing lysine 27 with methionine (H3 K27M). The mechanisms underlying regional selectivity for H3 K27M mutations, which are found almost exclusively in DMG, are not well understood. Here, we use a conditional knock-in mouse model to probe the postnatal brain region-specific oncogenic effects of H3.3 K27M in embryonic GFAP+ neural stem cells. We show that H3.3 K27M reduces oligodendrocyte differentiation in a region-specific manner and increases postnatal proliferation of distinct progenitor states by brain region in vivo, selectively expanding the oligodendrocyte-lineage in the ventral pons. Cellular morphology, marker expression, and transcriptomic analyses of primary region-specific mouse OPC cultures demonstrated cell-intrinsic differences in wild-type brainstem and forebrain OPC differentiation dynamics. H3.3 K27M drives cell-autonomous increase in brainstem-derived OPC proliferation and disrupts intrinsic region-specific transcriptional programs, delaying differentiation in forebrain-derived OPCs and restraining full maturation of brainstem-derived OPCs. H3.3 K27M-mediated changes include brainstem-selective upregulation of genes in Bmp, Wnt, and Notch pathways that are relevant in DMG pathogenesis. Our findings reveal that H3.3 K27M differentially disrupts cell-autonomous regional oligodendrocyte development, which may provide an opportunistic window for brainstem-selective gliomagenesis.

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Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [RNA-seq]

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A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M III

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-B overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

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A Novel Mouse Model of Diffuse Midline Glioma Initiated in Neonatal Oligodendrocyte Progenitor Cells Highlights Cell- of-origin Dependent Effects of H3K27M II

Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A overexpression, along with p53 deletion, resulted in gliomas. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. Interestingly, H3K27 trimethylation was decreased with H3.3K27M induction even in Olig2+ cells. Therefore, we need to find if there is transcriptional changes for the tumorigenesis with H3.3K27M in Olig2+ cells.

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Project description:Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is increased when tumorigenesis is initiated in Nestin+ cells. Therefore, we need to find how the tumorigenic effects of H3.3K27M are more oncogenic in Nestin+ cells than Olig2+ cells.

2021-10-05 | GSE184934 | GEO

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Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation

Project description:Characterisation of a new subgroup of DMG lacking H3-K27M mutation that is defined by H3K27me3 loss and EZHIP overexpression that can be detected by IHC. These tumors are distinct from EZHIP-positive posterior fossa ependymomas and are associated with a dismal prognosis. We propose that these EZHIP/H3-WT tumors need to be considered similar to canonical DIPG/DMG, thus extending the spectrum of DMG with PRC2 inhibition beyond H3-K27M mutation

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