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Local inhibition of PRC2 activity by histone H3.3K27M drives replication defects through misregulation of the JNK pathway [ChIP-seq]

ABSTRACT: Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Tumor cells carrying the mutation show a dramatic decrease in H3K27me3 levels due to physical inhibition of PRC2 methyltransferase activity. Here we use a C. elegans model to quantify the antagonistic effects of the H3.3K27M oncohistone on H3K27 trimethylation genome wide. We demonstrate that PRC2 is locally both simulated by H3K27me3 and inhibited by the oncohistone in a concentration-dependent manner.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE117531 | GEO | 2019/04/26

REPOSITORIES: GEO

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Local inhibition of PRC2 activity by histone H3.3K27M drives replication defects through misregulation of the JNK pathway [RNA-seq]

Project description:Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Tumor cells carrying the mutation show a dramatic decrease in H3K27me3 levels due to physical inhibition of PRC2 methyltransferase activity. Here we use a C. elegans model to quantify the antagonistic effects of the H3.3K27M oncohistone on H3K27 trimethylation genome wide. We demonstrate that PRC2 is locally both simulated by H3K27me3 and inhibited by the oncohistone in a concentration-dependent manner.

2019-04-26 | GSE117471 | GEO

The H3.3K27M oncohistone antagonizes reprogramming in Drosophila

Project description:Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In some cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that expression of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 domains are globally reduced with oncohistone expression, suggesting that previous developmental programs must be silenced for effective transformation. Strikingly, mis-expressed Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb Repressive Complex 1 components. Our results imply that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers.

2021-06-15 | GSE161919 | GEO

PRC2-indepdendent actions of H3.3K27M in embryonic stem cell differentiation

Project description:The histone H3 variant, H3.3, is localized at specific regions in the genome, especially promoters and active enhancers, and has been shown to play important roles in development. A lysine to methionine substitution in position 27 (H3.3K27M) is a main cause of Diffuse Intrinsic Pontine Glioma, a lethal type of pediatric cancer. H3.3K27M has a dominant-negative effect by inhibiting the Polycomb Repressor Complex 2 (PRC2) activity. Here, we studied the immediate, genome-wide, consequences of the H3.3K27M mutation independent of PRC2 activity. We developed Doxycycline (Dox)-inducible mouse embryonic stem cells (ESCs) carrying a single copy of WT-H3.3, H3.3K27M and H3.3K27L, all fused to HA. We performed RNA-Seq and ChIP-Seq at different timepoints following Dox in undifferentiated and differentiated ESCs. We find increased binding of H3.3 around transcription start sites in cells expressing both H3.3K27M and H3.3K27L compared with WT, but not in cells treated with PRC2 inhibitors. Differentiated cells carrying either H3.3K27M or H3.3K27L retain expression of ESC-active genes, in expense of expression of genes related to neuronal differentiation. Taken together, our data suggest that a modifiable H3.3K27 is required for proper histone incorporation and cellular maturation, independent of PRC2 activity.

2022-09-01 | GSE195789 | GEO

The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression

Project description:Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis. We performed chromatin-immunoprecipitation of H3K27me3, H3K4me3, and EZH2 in SF7761 and NSC cell lines. And do RNA-seq in SF7761, SF8828 and NSC cell lines. SF7761 and SF8628 cell lines from patients harboring the histone H3.3 K27M mutation were obtained from Hashizume et al. (2012). NSCs (N7800-100) were purchased from Invitrogen and cultured and maintained in NSC medium (A10509-01, StemPro NSC SFM, Invitrogen).

2014-09-20 | E-GEOD-61586 | biostudies-arrayexpress

H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers

Project description:Expression of histone H3.3K27M mutant proteins in diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and supports the proliferation of DIPG cells in part through silencing of tumor suppressor gene WT1.

2018-07-02 | GSE94834 | GEO

The H3.3K27M oncohistone antagonizes reprogramming in Drosophila

Project description:The H3.3K27M oncohistone antagonizes reprogramming in Drosophila

| PRJNA679825 | ENA

The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression

2014-09-20 | GSE61586 | GEO

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Project description:Diffuse intrinsic pontine gliomas (DIPG) are a deadly paediatric brain tumours, non-resectable due to brainstem localisation and diffusive growth. Patients with DIPG have a dismal prognosis of 9-12 months of survival with no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase in H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.33K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting the role in repression of these genes. In addition, genes previously reported as H3K27M-dependent become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor, chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

2023-10-05 | MSV000093052 | MassIVE

Local inhibition of PRC2 activity by histone H3.3K27M drives replication defects through misregulation of the JNK pathway

Project description:Local inhibition of PRC2 activity by histone H3.3K27M drives replication defects through misregulation of the JNK pathway

| PRJNA482403 | ENA

Cell-of-origin and Developmental Trajectories Cooperate to Determine Chromatin Landscapes in Histone-Mutant Diffuse Midline Gliomas

Project description:Diffuse midline gliomas (DMGs) are universally fatal pediatric brain tumors associated with mutations in genes encoding either histone H3.1 or histone 3.3, often substitution of methionine for lysine 27 (H3K27M). H3K27 is a critical determinant of chromatin state via methylation by Enhancer-of-Zeste-Homolog-2 (EZH2). Previous reports have suggested that the pathologically low levels of H3K27me3 found in histone-mutant DMGs result primarily from H3K27M inhibiting EZH2 directly, but recent reports have called this model into question. To better understand the chromatin landscape of DMGs, we applied CUT&RUN to patient-derived DMG cell lines. Remarkably, we find that the PRC2 activity is similar in DMGs and embryonic stem cells, suggesting a primitive cell-of-origin, despite transcriptionally active regions maintaining markers of both stem cells and differentiated cells. We also show that exogenous expression of H3.3M at physiological levels has little effect on H3K27me3 levels, that H3K27M can colocalize with H3K27me3 in vivo and that the H3.3K27M oncohistone does not show evidence of sequestering PRC2 components. Our results suggest that chromatin landscapes in DMGs are a consequence of a stem-like chromatin state that is retained despite activation of differentiation programs. Our findings have implications for understanding DMG gliomagenesis and therapeutic approaches centered on epigenome-modifying agents.

2020-09-08 | GSE118099 | GEO

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