The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE158143 | GEO | 2021/12/31
REPOSITORIES: GEO
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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 | GSE159070 | 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 | GSE159465 | 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 and HIST1H3B, leading to the expression of histone H3 in which lysine 27 is substituted with methionine (H3K27M) in nearly 80% of DIPGs. 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. Here, we describe a new 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 involving induction of the tumour suppressor protein p16INK4A. In agreement with this, we show that tumour cells with non-functional p16INK4A do not respond to EZH2 inhibitors. Genome-wide enrichment analyses show that several genes retain H3K27me3 even in the presence of H3K27M. Several of these genes are associated with high levels of H3K27me3 in the absence of H3K27M, whereas regions with low H3K27me3 levels tend to lose H3K27me3 upon H3K27M expression. Furthermore, we find significant overlap between genes that retain H3K27me3 in mouse and human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M positive DIPGs, and we propose a therapeutic strategy for these tumours using EZH2 inhibitors and expression of p16INK4A as a marker for stratifying potential responding tumours.
2017-08-31 | GSE71225 | 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 | GSE85387 | 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
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 | GSE85385 | 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 and HIST1H3B, leading to the expression of histone H3 in which lysine 27 is substituted with methionine (H3K27M) in nearly 80% of DIPGs. H3K27M inhibits 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 genomic loci are still H3K27me3 positive. Here, we describe a new 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 in vitro and in vivo tumour cell growth through a mechanism involving induction of the tumour suppressor protein p16INK4A. In agreement with this, we show that tumour cells with inactivated p16INK4A function do not respond to EZH2 inhibitors. By analysing genome-wide H3K27me3 enrichment profile in mouse DIPG model, we highlight distinct features of the loci that lose or retain H3K27me3 in H3K27M expressing cells. Taken together these results show that residual PRC2 activity is required for the proliferation of H3K27M positive DIPGs, and we propose a therapeutic strategy for these tumours using EZH2 inhibitors and expression of p16INK4A as a marker for stratifying potential responding tumours.
2017-08-31 | GSE71387 | GEO
Project description:The regulation of gene expression is controlled in part by post-translational modifications to histone proteins. Methylation at histone H3, lysine 27 (H3K27), which is catalyzed by Polycomb repressive complex 2 (PRC2), is associated with silenced chromatin. Previous studies have identified dysregulation of H3K27 methylation in pediatric diffuse intrinsic pontine gliomas (DIPGs), the majority of which feature mutation of lysine 27 to methionine. This “oncohistone” potently inhibits PRC2 activity and leads to a global reduction in H3K27 methylation. Similar to DIPG, posterior fossa type A (PFA) ependymomas also show low levels of H3K27 methylation. Although PFAs do not possess the H3K27M oncohistone mutation, they do show increased expression of Cxorf67. Interestingly, Cxorf67 contains a C-terminal sequence that resembles the sequence surrounding H3K27, and we find that this portion of Cxorf67 inhibits PRC2 activity to an even greater extent than the H3K27M oncohistone. Thus, we suggest re-naming Cxorf67 as EZHIP (Enhancer of Zeste Homologs Inhibitory Protein). Furthermore, when expressed in 293T cells, Cxorf67 interacts with several members of PRC2 and induces changes in H3K27 methylation patterns that mirror the changes in H3K27 methylation induced by expression of H3K27M. We propose that PFAs have dysregulated H3K27 methylation by a mechanism that involves inhibition of PRC2 by Cxorf67, which could drive tumorigenesis.
2019-04-09 | PXD013390 | Pride
Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brain tumor with a median survival of 10-15 months. Histone H3 is mutated in 80% of DIPGs, dictating tumor location, onset, and outcome. Therapeutic resistance remains a major obstacle to preventing tumor recurrence and is in part driven by cancer stem cells (CSCs), which exhibit self-renewal properties and tumorigenic potential. In previous studies, we have identified these proliferative and tumorigenic features in aldehyde dehydrogenase positive (ALDH+) CSCs in H3K27M mutant DIPG. We hypothesize that ALDH-mediated cancer stemness and resistance may in part be driven by H3K27M. ALDH1A3 expression was reduced in CRISPR-edited DIPG cells (SU-DIPG-XIII) where the H3K27M mutation had been removed (H3K27M-KO). Furthermore, these gained differentiation characteristics and lost their neurosphere-forming potential. The parental (H3K27M) and H3K27M-KO cells were also subjected to ionizing radiation to identify genes responsible for radioresistance in histone-mutated DIPG radioresistance. Nascent transcriptomes were obtained from these cells using bromouridine labeling and capture followed by sequencing (Bru-seq).
2023-08-30 | GSE211833 | GEO