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

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

PROVIDER: PRJNA905336 | ENA |

REPOSITORIES: ENA

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

2024-03-06 | GSE218717 | GEO

PRC2

Project description:PRC2

| PRJNA761389 | ENA

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

Deletion of RING1A/B and loss of H2AK119ub1 affects PRC2 occupancy and H3K27me3 genome-wide

Project description:The chromatin modifying activities inherent to polycomb repressive complexes PRC1 and PRC2 play an essential role in gene regulation, cellular differentiation, and development. However, the mechanisms by which these complexes recognize their target sites and function together to form repressive chromatin domains remain poorly understood. Recruitment of PRC1 to target sites has been proposed to occur through a hierarchical process, dependent on the prior nucleation of PRC2 and placement of H3K27me3. Here, using a de novo targeting assay in mouse embryonic stem cells we unexpectedly discover that PRC1-dependent H2AK119ub1 leads to the recruitment of PRC2 and H3K27me3 to effectively initiate a polycomb domain. Genetic ablation of catalytic subunit of the PRC1 complex (RINGA/B) and ChIP-seq analysis of PRC1 and PRC2 components confirmed genome-wide decreases in PRC2 occupancy and H3K27me3 levels at PRC target sites. This activity is restricted to variant PRC1 complexes and genetic ablation experiments reveal that targeting of the variant PCGF1/PRC1 complex by KDM2B to CpG islands is required for polycomb domain formation and normal development. Together these observations provide a surprising new PRC1-dependent logic for PRC2 occupancy and polycomb domain formation. RING1A-/-;RING1Bfl/fl ES cells were treated with 800M-BM-5M tamoxifen for 48hours and compared to untreated control cells by ChIP-seq for RING1B, SUZ12, EZH2 and H3K27me3.

2014-05-27 | E-GEOD-55697 | biostudies-arrayexpress

C10ORF12 modulates PRC2 histone methyltransferase activity and H3K27me3 levels.

Project description:The polycomb repressive complex 2 (PRC2) catalyzes the methylation of histone H3 on lysine 27 (H3K27) to generate trimethyl-H3K27 (H3K27me3) marks, thereby leading to a repressive chromatin state that inhibits gene expression. C10ORF12 was recently identified as a novel PRC2 interactor. Here, we show that C10ORF12 specifically interacts with PRC2 through its middle region (positions 619-718). C10ORF12 significantly enhances the histone methyltransferase activity of PRC2 in vitro and dramatically increases the total H3K27me3 levels in HeLa cells. C10ORF12 also antagonizes Jarid2, which is an auxiliary factor of the PRC2.2 subcomplex, to promote increased H3K27me3 levels in HeLa cells. Moreover, C10ORF12 alters the substrate preference of PRC2. These results indicate that C10ORF12 functions as a positive regulator of PRC2 and facilitates PRC2-mediated H3K27me3 modification of chromatin. These findings provide new insight into the roles of C10ORF12 in regulating the activity of the PRC2 complex.

| S-EPMC6889301 | biostudies-literature

PRC2-AgeIndex: a universal biomarker of aging and rejuvenation [WGBS]

Project description:DNA methylation (DNAm) is one of the most reliable biomarkers of aging across many mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, age-dependent DNAm gain is less specified. Multiple studies have demonstrated that polycomb repressive complex 2 (PRC2) targets are enriched among the CpG sites which gain methylation with age. However, systematic whole-genome examination of all PRC2 targets in the context of aging methylome as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, by analyzing DNAm data from different assays and from multiple young and old human and mouse tissues, we found that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We also estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the “PRC2-AgeIndex,” defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells. In addition, we demonstrate the application of this biomarker in the evaluation of different anti-aging interventions, including dietary restriction and partial epigenetic reprogramming.

2024-06-19 | GSE253985 | GEO

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