Single cell multi-omics profiling of H3-K27M DMG
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ABSTRACT:
PROVIDER: PRJNA764213 | ENA |
REPOSITORIES: ENA
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Project description:Multi-omics profiling of H3-K27M DMGs across different age groups and locations, using fresh single whole cell RNA-seq, scATACseq, spatial in situ sequencing, and WES/targeted exome sequencing.
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2020-03-20 | E-MTAB-8888 | biostudies-arrayexpress
Project description:Diffuse midline gliomas (DMG) are aggressive tumors with a poor prognosis. In this study, a technique called t-SNE analysis was used to cluster tumors based on their methylation profiles. DMG subtype with a co-occurrence of H3.3K27M and BRAF or FGFR1 mutations have been identified. This subtype has a more favorable prognosis, with a median overall survival of 3 years.
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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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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.
2026-05-22 | GSE310474 | GEO
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.
2026-05-22 | GSE310472 | GEO
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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Project description:In this study, we report that EZHIP and H3 K27M preferentially interact with an allosterically activated form of PRC2 in vivo. The formation of H3 K27M- and EZHIP-PRC2 complexes occurs at CpG islands containing H3K27me3 and impedes PRC2 and H3K27me3 spreading. Moreover, we find that H3 K27M inhibits PRC2 in trans and can reduce H3K27me3 levels independent of chromatin incorporation. While EZHIP is not found outside of placental mammals, we find that expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved molecular mechanism.
2020-10-12 | GSE151980 | GEO
Project description:The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease.
2024-11-20 | GSE268776 | GEO
Project description:The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease.
2024-11-20 | GSE268775 | GEO