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

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

PROVIDER: PRJNA374553 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5250900_1.fastq.gz	Fastqsanger.gz
	SRR5250900_2.fastq.gz	Fastqsanger.gz
	SRR5250910_1.fastq.gz	Fastqsanger.gz
	SRR5250910_2.fastq.gz	Fastqsanger.gz
	SRR5250901_1.fastq.gz	Fastqsanger.gz

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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.

2018-07-02 | GSE94834 | 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 human 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 contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.

| S-EPMC6033537 | biostudies-literature

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

PRC2 facilitates the regulatory topology required for poised enhancer function during pluripotent stem cell differentiation [4C-seq]

Project description:Poised enhancers marked by H3K27me3 in pluripotent cells were previously proposed to facilitate the establishment of somatic expression programs upon embryonic stem cell (ESC) differentiation. However, the functional relevance and mechanism of action of poised enhancers remain unknown. Here, we use genetic deletions to demonstrate that poised enhancers are necessary for the induction of major anterior neural regulators. Mechanistically, poised enhancers enable RNA Polymerase II recruitment to their cognate promoters upon differentiation. Interestingly, poised enhancers already establish physical interactions with their target genes in ESC in a Polycomb repressive complex 2 (PRC2) dependent manner. Loss of PRC2 led to neither the activation of poised enhancers nor the induction of their putative target genes in undifferentiated ESC. In contrast, loss of PRC2 severely and specifically compromised the induction of major anterior neural genes representing poised enhancer targets. Overall, our work illuminates a novel function for polycomb proteins, which we propose facilitate neural induction by providing major anterior neural loci with a permissive regulatory topology.

2017-02-11 | GSE89208 | GEO

PRC2 facilitates the regulatory topology required for poised enhancer function during pluripotent stem cell differentiation [ChIP-seq]

2017-02-11 | GSE89209 | GEO

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

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

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PRC2 facilitates the regulatory topology required for poised enhancer function during pluripotent stem cell differentiation [RNA-seq EED]

2017-02-11 | GSE89210 | GEO

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

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

2019-04-26 | GSE117531 | GEO

Poised enhancers regulatory activity is topologically facilitated by polycomb [RNA-seq LHX5]

2017-10-26 | GSE89242 | GEO