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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147780 | 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 [RNA-seq]

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 | GSE148062 | GEO

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

2020-11-17 | GSE147782 | GEO

Cxorf67-FLAG co-immunoprecipitation analysis from 293T cells

Project description:The regulation of gene expression is controlled in part by post-translational modifications to histone proteins. Methylation at histone H3, lysine 27 (H3K27), which is catalyzed by Polycomb repressive complex 2 (PRC2), is associated with silenced chromatin. Previous studies have identified dysregulation of H3K27 methylation in pediatric diffuse intrinsic pontine gliomas (DIPGs), the majority of which feature mutation of lysine 27 to methionine. This “oncohistone” potently inhibits PRC2 activity and leads to a global reduction in H3K27 methylation. Similar to DIPG, posterior fossa type A (PFA) ependymomas also show low levels of H3K27 methylation. Although PFAs do not possess the H3K27M oncohistone mutation, they do show increased expression of Cxorf67. Interestingly, Cxorf67 contains a C-terminal sequence that resembles the sequence surrounding H3K27, and we find that this portion of Cxorf67 inhibits PRC2 activity to an even greater extent than the H3K27M oncohistone. Thus, we suggest re-naming Cxorf67 as EZHIP (Enhancer of Zeste Homologs Inhibitory Protein). Furthermore, when expressed in 293T cells, Cxorf67 interacts with several members of PRC2 and induces changes in H3K27 methylation patterns that mirror the changes in H3K27 methylation induced by expression of H3K27M. We propose that PFAs have dysregulated H3K27 methylation by a mechanism that involves inhibition of PRC2 by Cxorf67, which could drive tumorigenesis.

2019-04-09 | PXD013390 | Pride

Heterotypic nucleosomes and PRC2 drive DIPG oncogenesis

Project description:Diffuse intrinsic pontine gliomas (DIPG) are characterized by a heterozygous lysine-to-methionine mutation of histone H3 (H3K27M) that potently reduces Polycomb Repressive Complex 2 (PRC2) methylation of wild-type histone H3K27 (H3K27wt). The role of H3K27M and reduced H3K27wt methylation in DIPG pathogenesis has yet to be determined. Here, we have performed epigenomic profiling of patient-derived H3K27M mutant DIPG cells and demonstrate that H3K27M resides in nucleosomes with H3K27wt acetylation (H3K27ac), and H3K27M-H3K27ac containing nucleosomes co-localize with bromodomain proteins at actively transcribed genes and that PRC2 is excluded from H3K27M occupied regions. With respect to therapeutic implications of these observations, we demonstrate that pharmacologic bromodomain protein inhibition suppresses tumor growth in vivo. In total, our results indicate that H3K27M promotes H3K27ac at the expense of H3K27 methylation, and points to bromodomain protein inhibition as a clinical strategy for treating DIPG.

2017-02-27 | GSE78801 | 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

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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]

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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]

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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

Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis

Project description:High-throughput sequencing of numerous patient samples has identified a myriad of frequent mutations of epigenetic regulators in human cancers, including recently discovered mutations in histone-encoding genes. Lysine-to-methionine mutations such as H3K27M and H3K36M share a common mechanism of inhibiting methylation pathways at the genome-wide level to promote tumorigenesis. However, the mechanism underlying the molecular and cellular changes due to H3G34 alterations is yet to be determined. H3G34 itself is not post-translationally modified; however, G34 lies in close proximity to K36, which undergoes methylation during transcriptional elongation. In Hela cells, H3.3G34L/W mutations have no effect on global levels of methylation on H3K36, H3K27, or other major methylation sites on endogenous histone H3, which include both H3.3 and the canonical H3.1/H3.2 proteins. However, long exposures of the blots revealed that methylation on the ectopic Flag-H3.3 proteins are affected by G34 mutations: with di- and trimethylation on H3K36 and H3K27ac reduced whereas H3K27me3 increased in the G34L and G34W mutated H3.3 compared to the WT H3.3. ChIP-seq results showed that mutations of H3.3G34 affect methylation on H3K36 and H3K27 in cis. G34L/W mutants abolish SETD2 methylation of H3K36. In contrast, the enzymatic activities of both EZH2 and p300 on H3K27 are not affected by G34 mutations. Consistent with changes in H3K27me3 and H3K36m3 levels, we found increased binding of PRC2 (EZH2, SUZ12 and EED) and PRC1 complex components (CBX8 and RING2) and reduced binding of H3.3K36me3 reader such as ZMYND11 to the G34 mutants. In summary, our study revealed that histone H3.3 G34 mutations alter histone K36 and K27 methylation in cis, and affect the binding of readers specific to K36 or K27 methylation.

2018-04-26 | GSE110389 | GEO

Histone lysine-to-methionine mutation reprograms the histone methylation landscape and contributes to pleiotropic development in Arabidopsis

Project description:This study investigated the effect of expressing transgenic H3 with K36M missense mutations. We uncovered pleiotropic phenotypic defects and a strong loss of endogenous H3K36 methylation in all forms (me1,me2,me3)

2017-06-16 | GSE92449 | GEO

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