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

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

PROVIDER: PRJNA482253 | ENA |

REPOSITORIES: ENA

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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

Local inhibition of PRC2 activity by histone H3.3K27M drives replication defects through misregulation of the JNK pathway [ChIP-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 | GSE117531 | GEO

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

2019-04-26 | GSE117471 | GEO

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

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

| PRJNA482407 | ENA

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

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

2019-04-25 | GSE117533 | 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

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

H3.3K27M-induced chromatin changes drive ectopic replication through misregulation of the JNK pathway in C. elegans.

Project description: Not available

| S-EPMC6555832 | biostudies-literature

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

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

| PRJNA374553 | ENA

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

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