Multi-omic analysis of cell-of-origin and epigenomic state in pediatric H3K27M gliomas
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ABSTRACT:
PROVIDER: PRJNA779720 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16976600.fastq.gz | Fastqsanger.gz | |||
| SRR16976600_1.fastq.gz | Fastqsanger.gz | |||
| SRR16976600_2.fastq.gz | Fastqsanger.gz | |||
| SRR16976601.fastq.gz | Fastqsanger.gz | |||
| SRR16976601_1.fastq.gz | Fastqsanger.gz |
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Project description:Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations, and molecular profiles. The contribution of the cell-of-origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte-precursor-like cells (OPC). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, while H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, while other epigenetic changes are mainly contingent on the cell-of-origin chromatin state and cycling rate.
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Project description:Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations, and molecular profiles. The contribution of the cell-of-origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte-precursor-like cells (OPC). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, while H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, while other epigenetic changes are mainly contingent on the cell-of-origin chromatin state and cycling rate.
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Project description:It is not known whether midline pediatric gliomas driven by Histone 3 K27M mutations (oncohistones) or EZHIP expression (oncohistone-mimics) share a common cell-of-origin, or arise from distinct cell types with unique vulnerabilities to PRC2 inhibition and partner alterations. Here, we define the etiological and oncogenic relationship between pediatric midline gliomas characterized by inhibition of K27M and K27M-like oncohistones. We assemble an extensive reference for gliogenesis from the developing mouse and human fetal brain. With bulk and single-cell transcriptomics and epigenomics, we profiled a large cohort of primary tumors comprising H3.1K27M and H3.3K27M pontine gliomas, H3.3K27M thalamic gliomas, and EZHIP+ posterior fossa ependymomas. We focus on differences across axes of location (thalamus vs. pons vs. posterior fossa), tumor type (diffuse midline gliomas vs. ependymomas), and oncohistone (H3.1/2K27M vs. H3.3K27M vs. EZHIP). We use tumor molecular features to delineate transcriptional states and cell-of-origin in each entity. Finally, we use culture models in isogenic contexts to interrogate the effect of each oncohistone or mimic.
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Project description:Gliomas bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors. H3K27M mutant tumors display unique epigenomes with global loss of the chromatin repressive H3K27 trimethylation mark. Here, we generated a syngeneic H3K27M mouse model to study the dependence upon amino acid (AA) metabolism by performing an AA drop out screen. H3K27M mutant cells, but not histone wildtype cells, were highly dependent on the amino acid, methionine. Interrogating the methionine cycle dependency through an siRNA screen identified the enzyme Methionine Adenosyltransferase 2A (MAT2A), which catalyzes production of S-adenosylmethionine (SAM), a methyl donor. Sensitivity to MAT2A loss in H3K27M mutant cells was not mediated through the canonical mechanism of MTAP deletion; instead, H3K27M mutant cells have lower MAT2A protein levels, which is mediated by Adenosylmethionine Decarboxylase 1 (AMD1) production of decarboxylated SAM (dcSAM). MAT2A loss induces global depletion of H3K36me3, a potent chromatin mark of transcriptional elongation, as evaluated by quantitative chromatin immunoprecipitation with reference exogenous genome sequencing (ChIP-Rx-Seq) in multiple DIPG lines. Tandem H3K36me3 ChIP-Rx-seq and RNA-seq identified several oncogenic and developmental transcriptional programs associated with MAT2A loss. Moreover, inducible knockdown of MAT2A or methionine-restricted diets (MR) extended survival in both syngeneic and patient-derived xenograft models (PDXs) in vivo. Collectively, our results provide novel connections between AA metabolism and the epigenome in H3K27M gliomas, suggesting that MAT2A, a central regulator of methionine metabolism, presents exploitable therapeutic vulnerabilities in H3K27M gliomas.
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Project description:A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
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