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H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE147783 | GEO | 2020/11/17

REPOSITORIES: GEO

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H3K27M in Gliomas Causes a One-Step Decrease in H3K27 Methylation and Reduced Spreading within the Constraints of H3K36 Methylation.

Project description:The discovery of H3K27M mutations in pediatric gliomas marked a new chapter in cancer epigenomics. Numerous studies have investigated the effect of this mutation on H3K27 trimethylation, but only recently have we started to realize its additional effects on the epigenome. Here, we use isogenic glioma H3K27M+/- cell lines to investigate H3K27 methylation and its interaction with H3K36 and H3K9 modifications. We describe a "step down" effect of H3K27M on the distribution of H3K27 methylation: me3 is reduced to me2, me2 is reduced to me1, whereas H3K36me2/3 delineates the boundaries for the spread of H3K27me marks. We also observe a replacement of H3K27me2/3 silencing by H3K9me3. Using a computational simulation, we explain our observations by reduced effectiveness of PRC2 and constraints imposed on the deposition of H3K27me by antagonistic H3K36 modifications. Our work further elucidates the effects of H3K27M in gliomas as well as the general principles of deposition in H3K27 methylation.

| S-EPMC7703850 | biostudies-literature

H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [WGBS]

Project description:The discovery of H3K27M mutations in pediatric gliomas marked a new chapter in cancer epigenetics. Numerous studies have investigated the effect of this mutation on H3K27 trimethylation, but only recently have we started to realize its additional effects on the epigenome. Here, we use isogenic glioma H3K27M(+/-) cell lines to investigate H3K27 methylation and its interaction with H3K36 and H3K9 modifications. We describe a “Step Down” effect of H3K27M on the distribution of H3K27 methylation: me3 is reduced to me2, me2 is reduced to me1, while H3K36me2/3 delineate the boundaries for the spread of H3K27me marks. We also observe a replacement of H3K27me2/3 silencing by H3K9me3. Using a computational simulation, we explain our observations by reduced effectiveness of PRC2 and constraints imposed on deposition of H3K27me by antagonistic H3K36 modifications. Our work further elucidates the effect of H3K27M in gliomas, as well as general principles of deposition of H3K27 methylation.

2020-11-17 | GSE147782 | GEO

H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [RNA-seq]

2020-11-17 | GSE148062 | GEO

H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [ChIP-seq]

2020-11-17 | GSE147780 | GEO

H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation

Project description:H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation

| PRJNA616357 | ENA

H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [WGBS]

Project description:H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [WGBS]

| PRJNA616360 | ENA

H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [RNA-seq]

Project description:H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [RNA-seq]

| PRJNA622975 | ENA

H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [ChIP-seq]

Project description:H3K27M in Gliomas Causes a One-step Decrease in H3K27 Methylation and Reduced Spreading Within the Constraints of H3K36 Methylation [ChIP-seq]

| PRJNA616361 | ENA

H3K36 methylation antagonizes PRC2-mediated H3K27 methylation.

Project description:H3K27 methylation mediated by the histone methyltransferase complex PRC2 is critical for transcriptional regulation, Polycomb silencing, Drosophila segmentation, mammalian X chromosome inactivation, and cancer. PRC2-mediated H3K27 methylation can spread along the chromatin and propagate the repressive chromatin environment; thus, chromatin components that antagonize the activity of PRC2 are important for restraining Polycomb silencing. Here we report that in HeLa cells, H3 histones unmethylated at Lys-36 are mostly methylated at Lys-27, with the exception of newly synthesized H3. In addition, K27me3 rarely co-exists with K36me2 or K36me3 on the same histone H3 polypeptide. Moreover, PRC2 activity is greatly inhibited on nucleosomal substrates with preinstalled H3K36 methylation. These findings collectively identify H3K36 methylation as a chromatin component that restricts the PRC2-mediated spread of H3K27 methylation. Finally, we provide evidence that the controversial histone lysine methyltransferase Ash1, a known Trithorax group protein that antagonizes Polycomb silencing in vivo, is an H3K36-specific dimethylase, not an H3K4 methylase, further supporting the role of H3K36 methylation in antagonizing PRC2-mediated H3K27 methylation.

| S-EPMC3048685 | biostudies-literature

Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.

Project description:High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.

| S-EPMC6521975 | biostudies-literature

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