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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE117533 | GEO | 2019/04/25

REPOSITORIES: GEO

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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: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

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: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 [RNA-seq]

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

| PRJNA482253 | ENA

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

PRC2-independent 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 (specifically Diffuse Midline Glioma, K27M-mutant), 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 extra copy of WT-H3.3, H3.3K27M and H3.3K27L, all fused to HA. We performed RNA-Seq and ChIP-Seq at different times following Dox induction 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.

| S-EPMC9976889 | biostudies-literature

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

Alternative splicing decouples local from global PRC2 activity

Project description:PRC2 mediates epigenetic maintenance of gene silencing in eukaryotes via methylation of H3K27. This complex interacts with sets of accessory factors forming two distinct subtypes (PRC2.1 and PRC2.2) that differ in their action and chromatin targeting mechanisms. However, the underlying molecular mechanisms orchestrating PRC2 assembly are not yet understood. Here, we report the identification of an alternative splicing event involving that alternative splicing of the PRC2 core component SUZ12 exon 4 which generates two isoforms coexisting in the same cell in virtually all tissues and developmental stages. Skipping this exon generates a previously uncharacterized isoform (SUZ12S) that forces the formation of the PRC2.1 subtype and favors PRC2 dimerization. Our results suggest that while SUZ12L is needed for maintenance of global H3K27 methylation levels, While SUZ12S is necessary and sufficient to ensure correct repression of Polycomb target genes via promoter-proximal H3K27me3 deposition, the full-length SUZ12L isoform is needed for maintenance of global H3K27 methylation levels. Lastly, we show that mouse embryonic stem cells lacking either of the two isoforms display impaired exit from pluripotency upon differentiation stimulus. Our findings thus reveal evidence for the existence of a physiological mechanism regulating PRC2 assembly and higher order interactions, with an impact on H3K27 methylation and gene repression.

2024-03-18 | GSE223666 | GEO

Conservation of replication timing reveals global and local regulation of replication origin activity.

Project description:DNA replication initiates from defined locations called replication origins; some origins are highly active whereas others are dormant and rarely used. Origins also differ in their activation time resulting in particular genomic regions replicating at characteristic times and in a defined temporal order. Here we report the comparison of genome replication in four budding yeast species: Saccharomyces cerevisiae, S. paradoxus, S. arboricolus and S. bayanus. First, we find that the locations of active origins are predominantly conserved between species, whereas dormant origins are poorly conserved. Second, we generated genome-wide replication profiles for each of these species and discovered that the temporal order of genome replication is highly conserved. Therefore, active origins are not only conserved in location, but also activation time. Only a minority of these conserved origins show differences in activation time between these species. To gain insight as to the mechanisms by which origin activation time is regulated we generated replication profiles for a S. cerevisiae / S. bayanus hybrid strain and find that there are both local and global regulators of origin function. Measurement of genome replication time from 4 budding yeast species (Saccharomyces cerevisiae, S. paradoxus, S. arboricolus and S. bayanus) and a hybrid (between Saccharomyces cerevisiae and S. bayanus). For each strain two samples were analysed: a replicating sample (from S phase) and a non-replicating sample (from G2 phase) The reference genome sequences for each yeast species are available as Series supplementary file [sac*.fa]

2012-06-19 | E-GEOD-36045 | biostudies-arrayexpress

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