The H3K36me2 writer-reader dependency in H3K27M-DIPG
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727843 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14459215.fastq.gz | Fastqsanger.gz | |||
| SRR14459216.fastq.gz | Fastqsanger.gz | |||
| SRR14459217.fastq.gz | Fastqsanger.gz | |||
| SRR14459218.fastq.gz | Fastqsanger.gz | |||
| SRR14459219.fastq.gz | Fastqsanger.gz |
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Project description:The lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, displacement of methylation at lysine 27 of histone H3 (H3K27me2/3), and thus promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.
2021-07-21 | GSE174006 | GEO
Project description:The H3K36me2 writer-reader dependency in H3K27M-DIPG
| PRJNA727843 | ENA
Project description:Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG.
| S-EPMC8279504 | biostudies-literature
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.
2018-08-31 | GSE118954 | GEO
Project description:Diffuse intrinsic pontine gliomas (DIPG) are characterized by a heterozygous lysine-to-methionine mutation of histone H3 (H3K27M) that potently reduces Polycomb Repressive Complex 2 (PRC2) methylation of wild-type histone H3K27 (H3K27wt). The role of H3K27M and reduced H3K27wt methylation in DIPG pathogenesis has yet to be determined. Here, we have performed epigenomic profiling of patient-derived H3K27M mutant DIPG cells and demonstrate that H3K27M resides in nucleosomes with H3K27wt acetylation (H3K27ac), and H3K27M-H3K27ac containing nucleosomes co-localize with bromodomain proteins at actively transcribed genes and that PRC2 is excluded from H3K27M occupied regions. With respect to therapeutic implications of these observations, we demonstrate that pharmacologic bromodomain protein inhibition suppresses tumor growth in vivo. In total, our results indicate that H3K27M promotes H3K27ac at the expense of H3K27 methylation, and points to bromodomain protein inhibition as a clinical strategy for treating DIPG.
2017-02-27 | GSE78801 | GEO
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
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
Project description:Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique lysine-to-methionine substitution in histone-3 at lysine 27 (H3K27M). We show here that the specific Polycomb targets disrupted by H3K27M and resultant oncogenic state is dependent on both the variant of histone-3 and the cell- context in which the mutation occurs. Through primary DIPG tumor characterization and isogenic expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending on whether it occurs in genes encoding H3.3 or H3.1. By comparison to non-malignant pediatric pontine tissue, we create a molecular map for DIPG, identifying and functionally validating both shared and subgroup-specific pathophysiology. Directly comparing the earliest events of H3K27M tumor initiation in putative cells-of-origin demonstrates that DIPG arises only from an oligodendrocyte precursor cell state.
2019-10-03 | GSE126319 | 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: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