Histone methyltransferase Ezh2 negatively regulates NK cell terminal maturation and function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA733052 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14664500_1.fastq.gz | Fastqsanger.gz | |||
| SRR14664500_2.fastq.gz | Fastqsanger.gz | |||
| SRR14664501_1.fastq.gz | Fastqsanger.gz | |||
| SRR14664501_2.fastq.gz | Fastqsanger.gz | |||
| SRR14664502_1.fastq.gz | Fastqsanger.gz |
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Project description:Deletion of Ezh2 promotes NK cell terminal differentiation and cytotoxicity with increased IFN-γ production by a potential target Pbx1.
2021-05-28 | GSE175599 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE41651: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [expression] GSE41652: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [ChIP-seq] Refer to individual Series
2012-11-15 | E-GEOD-41653 | biostudies-arrayexpress
Project description:Our previous work indicated that the Enhancer of Zeste Homolog 2 (Ezh2) is a negative regulator of NK cell early differentiation and function by trimethylation of histone H3 lysine 27 (H3K27me3). Here, we deleted Ezh2 from immature NK and downstream progeny to explore its role in NK cell maturation by single-cell RNA sequencing (scRNA-seq). We identified six distinct NK stages based on transcriptional signature during the maturation of NK cells. Conditional deletion of Ezh2 in NK cells resulted in the maturation trajectory of NK cell arrested in CD11b SP stage 5 which is clustered with genes related to activating function of NK cells. Mechanistically, we speculated that Ezh2 plays a critical role in NK development by activating gene expression of the AP-1 superfamily independent of PRC2 function. Our results implied a novel role for the Ezh2-AP-1-Klrg1 axis to alter NK cell maturation trajectory and NK cell-mediated cytotoxicity.
2021-07-07 | GSE179186 | GEO
Project description:Inhibition of H3K27 methyltransferase EZH2 enhances osteogenic commitment of human mesenchymal progenitors and Ezh2 inactivation in mouse calvarial cells induces a post-proliferative state concomitant with increased production of a bone-related mineralizing extra-cellular matrix.
2015-09-30 | GSE73075 | GEO
Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.
2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress
Project description:Polycomb group proteins maintain gene expression patterns established during early development, with Polycomb Repressive Complex 2 (PRC2) methyltransferase a key regulator of cell differentiation, identity and plasticity. Consequently, extensive somatic mutations in PRC2, including gain- or loss- of function (GOF or LOF), are observed in human cancers. The regulation of chromatin structure by PRC2 is critically dependent on its EZH2 (Enhancer of Zeste Homolog 2) subunit, which catalyzes the methylation of histone H3 lysine 27 (H3K27). Recent structural studies of PRC2 revealed extensive conformational changes in the non-catalytic EZH2 N-terminal SANT-Binding Domain (SBD) during PRC2 activation, though the functional significance remains unclear. Here, we investigate how the SBD regulates PRC2 function. The domain is highly conserved in metazoans, dispensable for PRC2 assembly and chromatin localization, yet required for genome-wide histone H3K27 methylation. Further, we show that an intact SBD is necessary for the proliferation of EZH2-addicted lymphomas, and its deletion in the presence of EZH2 GOF mutations inhibits cancer cell growth. These observations provide new insights to the regulation of PRC2 activity in normal development and malignancy.
2025-01-13 | GSE286457 | GEO
Project description:Polycomb group proteins maintain gene expression patterns established during early development, with Polycomb Repressive Complex 2 (PRC2) methyltransferase a key regulator of cell differentiation, identity and plasticity. Consequently, extensive somatic mutations in PRC2, including gain- or loss- of function (GOF or LOF), are observed in human cancers. The regulation of chromatin structure by PRC2 is critically dependent on its EZH2 (Enhancer of Zeste Homolog 2) subunit, which catalyzes the methylation of histone H3 lysine 27 (H3K27). Recent structural studies of PRC2 revealed extensive conformational changes in the non-catalytic EZH2 N-terminal SANT-Binding Domain (SBD) during PRC2 activation, though the functional significance remains unclear. Here, we investigate how the SBD regulates PRC2 function. The domain is highly conserved in metazoans, dispensable for PRC2 assembly and chromatin localization, yet required for genome-wide histone H3K27 methylation. Further, we show that an intact SBD is necessary for the proliferation of EZH2-addicted lymphomas, and its deletion in the presence of EZH2 GOF mutations inhibits cancer cell growth. These observations provide new insights to the regulation of PRC2 activity in normal development and malignancy.
2025-01-13 | GSE286462 | GEO
Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
2022-02-17 | PXD029652 | Pride
Project description:Previously, we suggested a cytosolic role for the histone-methyltransferase Ezh2 in regulating lymphocyte activation, but molecular mechanisms underpinning this extra-nuclear function remained unclear. Here we show that Ezh2 regulates integrin-signaling and adhesion dynamics of neutrophils and dendritic cells. Ezh2 deficiency impaired integrin-dependent transendothelial migration of innate leukocytes and restricted disease progression in an animal model of multiple sclerosis. Direct methylation of talin, a key regulatory molecule in cell migration, by Ezh2 disrupted talin binding to F-actin and thereby promoted adhesion structure turnover. This regulatory effect was abolished by targeted disruption of Ezh2 interactions with Vav1. Our studies reveal a novel extra-nuclear function for Ezh2 in regulating adhesion dynamics with implications for leukocyte migration, immune responses and potentially pathogenic processes. Control and Ezh2-deficient bone marrow derived immature and mature dendritic cells were analyzed in triplicates
2015-03-09 | E-GEOD-60146 | biostudies-arrayexpress
Project description:Polycomb group proteins maintain gene expression patterns established during early development, with Polycomb Repressive Complex 2 (PRC2) methyltransferase a key regulator of cell differentiation, identity and plasticity. Consequently, extensive somatic mutations in PRC2, including gain- or loss- of function (GOF or LOF), are observed in human cancers. The regulation of chromatin structure by PRC2 is critically dependent on its EZH2 (Enhancer of Zeste Homolog 2) subunit, which catalyzes the methylation of histone H3 lysine 27 (H3K27). Recent structural studies of PRC2 revealed extensive conformational changes in the non-catalytic EZH2 N-terminal SANT-Binding Domain (SBD) during PRC2 activation, though the functional significance remains unclear. Here, we investigate how the SBD regulates PRC2 function. The domain is highly conserved in metazoans, dispensable for PRC2 assembly and chromatin localization, yet required for genome-wide histone H3K27 methylation. Further, we show that an intact SBD is necessary for the proliferation of EZH2-addicted lymphomas, and its deletion in the presence of EZH2 GOF mutations inhibits cancer cell growth. These observations provide new insights to the regulation of PRC2 activity in normal development and malignancy.
2025-01-13 | GSE286459 | GEO