The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [MeDIP-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA669009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12818100_1.fastq.gz | Fastqsanger.gz | |||
| SRR12818100_2.fastq.gz | Fastqsanger.gz | |||
| SRR12818101_1.fastq.gz | Fastqsanger.gz | |||
| SRR12818101_2.fastq.gz | Fastqsanger.gz | |||
| SRR12818102_1.fastq.gz | Fastqsanger.gz |
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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.
2021-12-31 | GSE159465 | GEO
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.
2021-12-31 | GSE158143 | GEO
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.
2021-12-31 | GSE159070 | GEO
Project description:The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential
| PRJNA667605 | ENA
Project description:The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [ChIP-Seq]
| PRJNA664120 | ENA
Project description:The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [RNA-Seq]
| PRJNA667611 | ENA
Project description:BackgroundNeurodevelopmental disorders increase brain tumor risk, suggesting that normal brain development may have protective properties. Mutations in epigenetic regulators are common in pediatric brain tumors, highlighting a potentially central role for disrupted epigenetic regulation of normal brain development in tumorigenesis. For example, lysine 27 to methionine mutation (H3K27M) in the H3F3A gene occurs frequently in Diffuse Intrinsic Pontine Gliomas (DIPGs), the most aggressive pediatric glioma. As H3K27M mutation is necessary but insufficient to cause DIPGs, it is accompanied by additional mutations in tumors. However, how H3K27M alone increases vulnerability to DIPG tumorigenesis remains unclear.ResultsHere, we used human embryonic stem cell models with this mutation, in the absence of other DIPG contributory mutations, to investigate how H3K27M alters cellular proliferation and differentiation. We found that H3K27M increased stem cell proliferation and stem cell properties. It interfered with differentiation, promoting anomalous mesodermal and ectodermal gene expression during both multi-lineage and germ layer-specific cell specification, and blocking normal differentiation into neuroectoderm. H3K27M mutant clones exhibited transcriptomic diversity relative to the more homogeneous wildtype population, suggesting reduced fidelity of gene regulation, with aberrant expression of genes involved in stem cell regulation, differentiation, and tumorigenesis. These phenomena were associated with global loss of H3K27me3 and concordant loss of DNA methylation at specific genes in H3K27M-expressing cells.ConclusionsTogether, these data suggest that H3K27M mutation disrupts normal differentiation, maintaining a partially differentiated state with elevated clonogenicity during early development. This disrupted response to early developmental cues could promote tissue properties that enable acquisition of additional mutations that cooperate with H3K27M mutation in genesis of DMG/DIPG. Therefore, this work demonstrates for the first time that H3K27M mutation confers vulnerability to gliomagenesis through persistent clonogenicity and aberrant differentiation and defines associated alterations of histone and DNA methylation.
| S-EPMC9153095 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-12-31 | GSE159071 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brain tumour that is located in the pons and primarily affects children. Whole-exome sequencing studies have identified recurrent driver mutations in H3F3A (H3.3) and HIST1H3B (H3.1), leading to the expression of histone H3 in which lysine 27 is substituted with methionine (H3K27M) in nearly 80% of DIPGs1-5. H3K27M has been shown to inhibit Polycomb Repressive Complex 2 (PRC2) activity by binding to its catalytic subunit EZH2, and although DIPGs with H3K27M mutation show global loss of H3 with trimethylated lysine 27 (H3K27me3), several genes retain H3K27me3 (Refs. 1-8). Here, we describe a mouse DIPG model in which H3K27M potentiates tumourigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M expressing tumours require PRC2 for proliferation. Furthermore, we demonstrate that small molecule EZH2 inhibitors abolish tumour cell growth through a mechanism that is dependent on the induction of the tumour suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets and are highly enriched for H3K27me3/PRC2/PRC1 in cells prior to H3K27M expression. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the mouse DIPG model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M positive DIPGs, and inhibition of EZH2 is as a potential therapeutic strategy for the treatment of these tumours.
2017-02-28 | GSE85388 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive brain tumour that is located in the pons and primarily affects children. Whole-exome sequencing studies have identified recurrent driver mutations in H3F3A (H3.3) and HIST1H3B (H3.1), leading to the expression of histone H3 in which lysine 27 is substituted with methionine (H3K27M) in nearly 80% of DIPGs1-5. H3K27M has been shown to inhibit Polycomb Repressive Complex 2 (PRC2) activity by binding to its catalytic subunit EZH2, and although DIPGs with H3K27M mutation show global loss of H3 with trimethylated lysine 27 (H3K27me3), several genes retain H3K27me3 (Refs. 1-8). Here, we describe a mouse DIPG model in which H3K27M potentiates tumourigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M expressing tumours require PRC2 for proliferation. Furthermore, we demonstrate that small molecule EZH2 inhibitors abolish tumour cell growth through a mechanism that is dependent on the induction of the tumour suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets and are highly enriched for H3K27me3/PRC2/PRC1 in cells prior to H3K27M expression. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the mouse DIPG model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M positive DIPGs, and inhibition of EZH2 is as a potential therapeutic strategy for the treatment of these tumours.
2017-02-28 | GSE85386 | GEO