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Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [CUT&RUN]

ABSTRACT: Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants was exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupted broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss led to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrated impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE239636 | GEO | 2024/04/29

REPOSITORIES: GEO

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Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [scRNA-Seq]

Project description:Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants was exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupted broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss led to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrated impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

2024-04-29 | GSE239637 | GEO

Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation [RNA-Seq]

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Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation

Project description:Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation. Middle down analysis of histone H3 WT or mutant

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2020-12-07 | PXD012347 | Pride

Affinify Purification of EZH2 and phosphodeficient EZH2 identifies phosphorylation dependent interactions of EZH2

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2018-07-03 | PXD010073 | Pride

Paramecium Polycomb Repressive Complex 2 physically interacts with the small RNA binding PIWI protein to repress transposable elements

Project description:Polycomb Repressive Complex 2 (PRC2) maintains transcriptionally silent genes in a repressed state via deposition of histone H3 K27 trimethyl (me3) marks. PRC2 has also been implicated in silencing transposable elements (TEs) yet how PRC2 is targeted to TEs remains unclear. To address this question, we performed tandem affinity purification combined with mass spectrometry and identified proteins that physically interact with the Paramecium Enhancer-of-zeste Ezl1 enzyme, which catalyzes H3K9me3 and H3K27me3 deposition at TEs. We show that the Paramecium PRC2 core complex comprises four subunits, each required in vivo for catalytic activity. We also identify PRC2 cofactors, including the RNA interference (RNAi) effector Ptiwi09, which are necessary to target H3K9me3 and H3K27me3 to TEs. We find that the physical interaction between PRC2 and the RNAi pathway is mediated by a RING finger protein and that small RNA recruitment of PRC2 to TEs is analogous to the small RNA recruitment of H3K9 methylation SU(VAR)3-9 enzymes.

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2017-12-26 | GSE108538 | GEO

Identification of JARID2/PRC2 interactome in human embryonic stem cells

Project description:JARID2 is an integral subunit of the chromatin modifier PRC2 (Polycomb Repressive Complex 2). PRC2 methylates lysine 27 in histone H3 and is required for human development. Mutaitons of PRC2 subunits have been frequently found in a variety of adult and pediatric cancer, suggesting that PRC2 critically regulates normal and cancer development. The goal of this project is to identify new regulator or co-factors of PRC2 and study their molecular interactions and activities in order to better understand function and regulation of PRC2 in normal and cancer development.

2020-08-04 | PXD015670 | Pride

Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

Project description:Polycomb Repressive Complex 2 (PRC2) plays an essential role in development by catalysing trimethylation of histone H3 lysine 27 (H3K27me3), resulting in gene repression. PRC2 consists of two sub-complexes, PRC2.1 and PRC2.2, in which the PRC2 core associates with distinct ancillary subunits such as MTF2 and JARID2, respectively. Both MTF2, present in PRC2.1, and JARID2, present in PRC2.2, play a role in core PRC2 recruitment to target genes in mouse embryonic stem cells (mESCs). However, it remains unclear how these distinct sub-complexes cooperate to establish H3K27me3 domains. Here, we combine a range of Polycomb mutant mESCs with chemical inhibition of PRC2 catalytic activity, to systematically dissect their relative contributions to PRC2 binding to target loci. We find that PRC2.1 and PRC2.2 mediate two distinct paths for recruitment, with mutually reinforced binding. Part of the cross-talk between PRC2.1 and PRC2.2 occurs via their catalytic product H3K27me3, which is bound by the PRC2 core-subunit EED, thereby mediating a positive feedback. Strikingly, removal of either JARID2 or H3K27me3 only has a minor effect on PRC2 recruitment, whereas their combined ablation largely attenuates PRC2 recruitment. This strongly suggests an unexpected redundancy between JARID2 and EED-H3K27me3-mediated recruitment of PRC2. Furthermore, we demonstrate that all core PRC2 recruitment occurs through the combined action of MTF2-mediated recruitment of PRC2.1 to DNA and PRC1-mediated recruitment of JARID2-containing PRC2.2. Both axes of binding are supported by EED-H3K27me3 positive feedback, but to a different degree. Finally, we provide evidence that PRC1 and PRC2 mutually reinforce reciprocal binding. Together, these data disentangle the interdependent and cooperative interactions between Polycomb complexes that are important to establish Polycomb repression at target sites.

2021-09-22 | PXD020684 | Pride

Two distinct functional axes of positive feedback-enforced PRC2 recruitment in mouse embryonic stem cells

2020-08-07 | PXD014290 | Pride

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