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Epigenetic changes in mouse neuronal stem cells with histone H3K27M mutations [ChIP-seq]

ABSTRACT: Epigenetic changes in mouse neuronal stem cells with histone H3K27M mutations [ChIP-seq]

PROVIDER: PRJNA558796 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9908362.fastq.gz	Fastqsanger.gz
	SRR9908363.fastq.gz	Fastqsanger.gz
	SRR9908364.fastq.gz	Fastqsanger.gz
	SRR9908365.fastq.gz	Fastqsanger.gz
	SRR9908366.fastq.gz	Fastqsanger.gz

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Epigenetic changes in mouse neuronal stem cells and human DIPG cells with histone H3K27M mutations

Project description:Epigenetic changes in mouse neuronal stem cells and human DIPG cells with histone H3K27M mutations

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Epigenetic changes in human DIPG cells with histone H3K27M mutations [ATAC-seq]

Project description:Epigenetic changes in human DIPG cells with histone H3K27M mutations [ATAC-seq]

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Epigenetic changes in mouse neuronal stem cells with histone H3K27M mutations [ChIP-seq]

Project description:H3.3K27M mutations or H3.3 WT were expressed in in neuronal stem cells (Nsc) derived from p16Ink4a/p14Arf knockout (KO) animal. Genomic changes in H3K27me3, H3K27ac and H3K4me3 were assessed between H3.3K27M and H3.3WT cells.

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The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [MeDIP-Seq]

Project description:Lysine 27 to methionine mutation (H3K27M) of the H3F3A gene, which encodes the variant histone H3.3, is found in the majority of Diffuse Intrinsic Pontine Gliomas (DIPGs). DIPGs are the most aggressive form of pediatric gliomas and have a median survival of <1 year from diagnosis. As H3K27M mutation is necessary but not sufficient to cause DIPGs, it is accompanied by several other mutations in tumors. However, the mechanisms by which H3K27M increases vulnerability to DIPG tumorigenesis, while expected to involve altered epigenetic regulation is unclear. Thus, in this work we built pairs of isogenic human embryonic stem cell lines with versus without this mutation, in the absence of other DIPG contributory mutations, to investigate mechanisms by which H3K27M mutation could affect cellular proliferation and differentiation and how these were related to alterations in the transcriptome, H3K27me3, and the DNA methylome. We found that H3K27M increased stem cell proliferation and interfered with differentiation, resulting in loss of most H3K27me3 and resulting in anomalous onset of expression of developmental genes during multilineage or directed differentiation. This work suggests mechanisms by which H3K27M mutation influences stem cell properties, contributing to DIPG tumorigenesis.

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The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [RNA-Seq]

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The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [ChIP-Seq]

2021-12-31 | GSE158143 | GEO

Inhibition of SP/KLF transcription regulatory network and histone deacetylases acts synergistically against H3K27M-DIPG

Project description:Diffuse intrinsic pontine gliomas (DIPGs), frequently harboring H3K27M mutations, are lethal pediatric brain tumors within no effective treatment. Here our epigenomic analyses uncover a marked enrichment of the SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. We show that SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized Mithramycin analog, significantly suppresses the proliferation and invasiveness of H3K27M-DIPG cells. In a screen of epigenetic drugs, we find that histone deacetylase inhibitors (HDACi) synergize with EC-8042 to suppress H3K27M-DIPG cell growth. The RNA-seq in SU-DIPG-IV and SU-DIPG-XVII cells after treated with DMSO, EC-8042, vorinostat and combination vorinostat with EC-8042 revealed that HDACi activates transcriptional programs that enhance tumor adaptability and invasiveness, an effect counteracted by EC-8042. And EC-8042 in combination with HDACi synergistically represses the expression of cell cycle-associated genes and therefore suppresses H3K27M-DIPG cell proliferation, inhibiting tumor progression in orthotopic xenograft models. Transcriptomic analysis further supports that the combination treatment drives transcriptional programs correlating with favorable prognosis in DIPG patients. Therefore, our regulome profiling in H3K27M-DIPGs has provided mechanistic insights into HDACi resistance and a proof-of-concept for novel targeting therapeutics.

2025-02-20 | GSE255013 | GEO

Epigenetic changes in mouse neuronal stem cells and human DIPG cells with histone H3K27M mutations

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-06-24 | GSE135419 | GEO

MAT2A and methionine dependency are indispensible for H3K27M mutant gliomas.

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.

2022-01-28 | GSE160006 | GEO

Cancer Associated Histone Mutations

Project description:Cancer Associated Histone Mutations

| PRJNA867413 | ENA