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EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition.

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

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE218717 | GEO | 2024/03/06

REPOSITORIES: GEO

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EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition [RNA-seq]

Project description:We have modelled several tumor-associated PRC2 mutations in a single isogenic system in order to reveal their comparative impacts on chromatin and transcription. We have also explored the link between EZH2 mutational status and abnormal H3K27 methylation in a unique longitudinal cohort of follicular lymphoma (FL) patient samples.

2024-03-06 | GSE218715 | GEO

EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition [ChIP-Seq/Cut&Run-Seq]

2024-03-06 | GSE218716 | GEO

EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition.

Project description:EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition.

| PRJNA905334 | ENA

EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition [RNA-seq]

Project description:EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition [RNA-seq]

| PRJNA905335 | ENA

EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition [ChIP-Seq/Cut&Run-Seq]

Project description:EZH2 gain-of-function mutations distort H3K27me3 landscapes and transform transcriptional responses to PRC2 inhibition [ChIP-Seq/Cut&Run-Seq]

| PRJNA905336 | ENA

Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.

Project description:Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.

| S-EPMC3951439 | biostudies-literature

EZH2 W113C is a gain-of-function mutation in B-cell lymphoma enabling both PRC2 methyltransferase activation and tazemetostat resistance.

Project description:Polycomb repressive complex 2 (PRC2) suppresses gene transcription by methylating lysine 27 of histone H3 (H3K27) and plays critical roles in embryonic development. Among the core PRC2 subunits, EZH2 is the catalytic subunit and EED allosterically activates EZH2 upon binding trimethylated H3K27 (H3K27me3). Activating mutations on Y641, A677, and A687 within the enzymatic SET (Su(Var)3 to 9, Enhancer-of-zeste, and Trithorax) domain of EZH2 have been associated with enhanced H3K27me3 and tumorigenicity of many cancers including B-cell lymphoma and melanoma. To tackle the critical residues outside the EZH2 SET domain, we examined EZH2 mutations in lymphoma from cancer genome databases and identified a novel gain-of-function mutation W113C, which increases H3K27me3 in vitro and in vivo and promotes CDKN2A silencing to a similar level as EZH2 Y641F. Different from other gain-of-function mutations, this mutation is located in the SET-activation loop at the EZH2 N terminus, which stabilizes the SET domain and facilitates substrate binding. This may explain how the W113C mutation increases PRC2 activity. Tazemetostat is a Food and Drug Administration-approved EZH2-binding inhibitor for follicular lymphoma treatment. Intriguingly, the W113C mutation leads to tazemetostat resistance in both H3K27 methylation and tumor proliferation. Another class of allosteric PRC2 inhibitor binding EED overcomes the resistance, effectively decreases H3K27me3, and blocks tumor proliferation in cells expressing EZH2 W113C. As this mutation is originally identified from lymphoma samples, our results demonstrated its activating characteristic and the deleterious consequence, provide insights on PRC2 regulation, and support the continued exploration of treatment optimization for lymphoma patients.

| S-EPMC10066557 | biostudies-literature

Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition.

Project description:Purpose: EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on multiple myeloma and prostate cancer.Experimental Design:In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in multiple myeloma cell lines, primary patient cells, and in a xenograft model. RNA-seq and ChIP-seq were performed to uncover the targets of UNC1999 in multiple myeloma. The efficacy of the combination therapy was validated in prostate cancer cell lines.Results: Proteasome inhibitors repressed EZH2 transcription via abrogation of the RB-E2F pathway, thereby sensitizing EZH2-dependent multiple myeloma cells to EZH1 inhibition by UNC1999. Correspondingly, combination of proteasome inhibitors with UNC1999, but not with an EZH2-specific inhibitor, induced synergistic antimyeloma activity in vitro Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells in vivo Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene NR4A1 Derepression of NR4A1 by UNC1999 resulted in suppression of MYC, which was enhanced by the combination with bortezomib, suggesting the cooperative blockade of PRC2 function. Notably, this combination also exhibited strong synergy in prostate cancer cells.Conclusions: Our results identify dual inhibition of EZH2 and EZH1 together with proteasome inhibition as a promising epigenetics-based therapy for PRC2-dependent cancers. Clin Cancer Res; 23(16); 4817-30. ©2017 AACR.

| S-EPMC5562278 | biostudies-literature

Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function.

Project description:Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.

| S-EPMC5777296 | biostudies-literature

PRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor.

Project description:A lysine-to-methionine mutation at lysine 27 of histone 3 (H3K27M) has been shown to promote oncogenesis in a subset of pediatric gliomas. While there is evidence that this "oncohistone" mutation acts by inhibiting the histone methyltransferase PRC2, the details of this proposed mechanism nevertheless continue to be debated. Recent evidence suggests that PRC2 must simultaneously bind both H3K27M and H3K27me3 to experience competitive inhibition of its methyltransferase activity. In this work, we used PRC2 inhibitor treatments in a transgenic H3K27M cell line to validate this dependence in a cellular context. We further used designer chromatin inhibitors to probe the geometric constraints of PRC2 engagement of H3K27M and H3K27me3 in a biochemical setting. We found that PRC2 binds to a bivalent inhibitor unit consisting of an H3K27M and an H3K27me3 nucleosome and exhibits a distance dependence in its affinity for such an inhibitor, which favors closer proximity of the 2 nucleosomes within a chromatin array. Together, our data precisely delineate fundamental aspects of the H3K27M inhibitor and support a model wherein PRC2 becomes trapped at H3K27M-H3K27me3 boundaries.

| S-EPMC6825254 | biostudies-literature

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