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

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

PROVIDER: PRJNA905334 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22407200_1.fastq.gz	Fastqsanger.gz
	SRR22407200_2.fastq.gz	Fastqsanger.gz
	SRR22407300_1.fastq.gz	Fastqsanger.gz
	SRR22407300_2.fastq.gz	Fastqsanger.gz
	SRR22407201_1.fastq.gz	Fastqsanger.gz

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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]

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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]

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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.

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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

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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.

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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.

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The transcriptional elongation factor CTR9 demarcates PRC2-mediated H3K27me3 domains by altering PRC2 subtype equilibrium.

Project description:CTR9 is the scaffold subunit in polymerase-associated factor complex (PAFc), a multifunctional complex employed in multiple steps of RNA Polymerase II (RNAPII)-mediated transcription. CTR9/PAFc is well known as an evolutionarily conserved elongation factor that regulates gene activation via coupling with histone modifications enzymes. However, little is known about its function to restrain repressive histone markers. Using inducible and stable CTR9 knockdown breast cancer cell lines, we discovered that the H3K27me3 levels are strictly controlled by CTR9. Quantitative profiling of histone modifications revealed a striking increase of H3K27me3 levels upon loss of CTR9. Moreover, loss of CTR9 leads to genome-wide expansion of H3K27me3, as well as increased recruitment of PRC2 on chromatin, which can be reversed by CTR9 restoration. Further, CTR9 depletion triggers a PRC2 subtype switch from the less active PRC2.2, to the more active PRC2.1 with higher methyltransferase activity. As a consequence, CTR9 depletion generates vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic distribution provide a unique mechanism that explains the transition from transcriptionally active chromatin states to repressive chromatin states and sheds light on the biological functions of CTR9 in development and cancer.

| S-EPMC8887485 | biostudies-literature

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