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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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			Action	DRS
	SRR7549332.fastq.gz	Fastqsanger.gz
	SRR7549333.fastq.gz	Fastqsanger.gz
	SRR7549334.fastq.gz	Fastqsanger.gz
	SRR7549335.fastq.gz	Fastqsanger.gz

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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

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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.

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

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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]

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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.

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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.

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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.

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

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

Project description:Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant cells show decreased levels and altered distribution of H3K27 trimethylation (H3K27me3). How these chromatin changes are established genome-wide and lead to tumorigenesis remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner. The heterochromatin changes result in extensive gene misregulation, and genetic screening identified upregulation of JNK as an underlying cause of the germcell aberrations. Moreover, JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishing C. elegans as a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.

| 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

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