Ezh2 shapes T cell plasticity to drive atherosclerosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1191439 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31531724.fastq.gz | Fastqsanger.gz | |||
| SRR31531725.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:Ezh2 shapes T cell plasticity to drive atherosclerosis II
| PRJNA1192301 | ENA
Project description:The activation and polarization of T cells play a crucial role in atherosclerosis and dictate athero-inflammation. The epigenetic enzyme enhancer of zeste homolog 2 (EZH2) mediates the tri-methylation of lysine27 on histone3 (H3K27me3) and is pivotal in controlling T cell responses. To detail the role of T cell-EZH2 in atherosclerosis, we used human carotid endarterectomy specimens to reveal plaque expression and geography of EZH2. Atherosclerosis-prone Apoe-deficient mice with CD4+ and/or CD8+ T cell-specific Ezh2 deletion (Ezh2cd4-KO, Ezh2cd8-KO) were analyzed to unravel T cell-Ezh2’s role in atherosclerosis and T cell-associated immune status.EZH2 expression is elevated in advanced human atherosclerotic plaques and primarily expressed in the T cell nucleus, suggesting the importance of canonical EZH2 function in atherosclerosis. Ezh2cd4-KO, but not Ezh2cd8-KO mice showed reduced atherosclerosis with less advanced plaques, which contained less collagen and macrophages, indicating that Ezh2 in CD4+ T cells drives atherosclerosis. In-depth analysis of CD4+ T cells of Ezh2cd4-KO mice revealed that absence of Ezh2 results in a type II immune response with increased Il-4 gene and protein expression in the aorta and lymphoid organs. In vitro, Ezh2-deficient T cells polarized macrophages towards an anti-inflammatory phenotype. scRNAseq of splenic T cells revealed that Ezh2-deficiency reduced naive, Ccl5+ and regulatory T cell populations and increased the frequencies of memory T cells and invariant natural killer T (iNKT) cells. Flow cytometric analysis identified a shift towards T helper 2 (Th2) effector CD4+ T cells in Ezh2cd4-KO mice and confirmed a profound increase in splenic iNKT cells with high expression of Plzf, the characteristic marker of the iNKT2 subset. Likewise, Zbtb16 (Plzf-encoding gene) transcripts were elevated in the aorta of Ezh2cd4-KO mice, suggesting an accumulation of iNKT2 cells in the plaque. H3K27me3-chromatin immunoprecipitation followed by qPCR showed that T cell-Ezh2 regulates the transcription of the Il-4 and Zbtb16 genes. Our study uncovers the importance of T cell-EZH2 in human and mouse atherosclerosis. Inhibition of Ezh2 in CD4+ T cells drives type II immune responses, resulting in an accumulation of iNKT2 and Th2 cells, memory T cells and anti-inflammatory macrophages that limit the progression of atherosclerosis. We performed scRNAseq of splenic T cells isolated from Ezh2cd4-KO and respective controls fed with Western type diet, to study T cells during atherosclerosis progression.
2025-02-13 | GSE283002 | GEO
Project description:The activation and polarization of T cells play a crucial role in atherosclerosis and dictate athero-inflammation. The epigenetic enzyme enhancer of zeste homolog 2 (EZH2) mediates the tri-methylation of lysine27 on histone3 (H3K27me3) and is pivotal in controlling T cell responses. To detail the role of T cell-EZH2 in atherosclerosis, we used human carotid endarterectomy specimens to reveal plaque expression and geography of EZH2. Atherosclerosis-prone Apoe-deficient mice with CD4+ and/or CD8+ T cell-specific Ezh2 deletion (Ezh2cd4-KO, Ezh2cd8-KO) were analyzed to unravel T cell-Ezh2’s role in atherosclerosis and T cell-associated immune status.EZH2 expression is elevated in advanced human atherosclerotic plaques and primarily expressed in the T cell nucleus, suggesting the importance of canonical EZH2 function in atherosclerosis. Ezh2cd4-KO, but not Ezh2cd8-KO mice showed reduced atherosclerosis with less advanced plaques, which contained less collagen and macrophages, indicating that Ezh2 in CD4+ T cells drives atherosclerosis. In-depth analysis of CD4+ T cells of Ezh2cd4-KO mice revealed that absence of Ezh2 results in a type II immune response with increased Il-4 gene and protein expression in the aorta and lymphoid organs. In vitro, Ezh2-deficient T cells polarized macrophages towards an anti-inflammatory phenotype. scRNAseq of splenic T cells revealed that Ezh2-deficiency reduced naive, Ccl5+ and regulatory T cell populations and increased the frequencies of memory T cells and invariant natural killer T (iNKT) cells. Flow cytometric analysis identified a shift towards T helper 2 (Th2) effector CD4+ T cells in Ezh2cd4-KO mice and confirmed a profound increase in splenic iNKT cells with high expression of Plzf, the characteristic marker of the iNKT2 subset. Likewise, Zbtb16 (Plzf-encoding gene) transcripts were elevated in the aorta of Ezh2cd4-KO mice, suggesting an accumulation of iNKT2 cells in the plaque. H3K27me3-chromatin immunoprecipitation followed by qPCR showed that T cell-Ezh2 regulates the transcription of the Il-4 and Zbtb16 genes. Our study uncovers the importance of T cell-EZH2 in human and mouse atherosclerosis. Inhibition of Ezh2 in CD4+ T cells drives type II immune responses, resulting in an accumulation of iNKT2 and Th2 cells, memory T cells and anti-inflammatory macrophages that limit the progression of atherosclerosis. We performed RNAseq on splenic CD4+ T cells isolated from Ezh2cd4-KO mice and Ezh2cd4-WT controls using an efficient sequencing method (Prime-seq).
2025-02-13 | GSE283191 | GEO
Project description:Somatic mtDNA Mutation Burden Shapes Metabolic Plasticity in Leukemogenesis
| PRJNA1167262 | ENA
Project description:Following antigen encounter by CD4 T cells, polarizing cytokines induce the expression of master regulators that control differentiation. Inactivation of the histone methyltransferase Ezh2 was found to specifically enhance T-helper (Th)1 and Th2 cell differentiation and plasticity. Ezh2 directly bound and facilitated correct expression of Tbx21 and Gata3 in differentiating Th1 and Th2 cells, accompanied by substantial tri-methylation at lysine 27 of histone 3 (H3K27-Me3). In addition, Ezh2 deficiency resulted in spontaneous generation of discrete IFN-γ and Th2 cytokine-producing populations in non-polarizing cultures, and under these conditions IFN-γ expression was largely dependent on enhanced expression of the transcription factor Eomesodermin. In vivo, Loss of Ezh2 caused increased pathology in a model of allergic asthma and resulted in progressive accumulation of memory phenotype Th2 cells. This study establishes a functional link between Ezh2 and transcriptional regulation of lineage-specifying genes in terminally differentiated CD4 T cells. Wild type and Ezh2 knock out unpolarized Th cells, Th1 cells and Th2 cells are profiled for mRNA expression
2013-09-11 | E-GEOD-50729 | biostudies-arrayexpress
Project description:Following antigen encounter by CD4 T cells, polarizing cytokines induce the expression of master regulators that control differentiation. Inactivation of the histone methyltransferase Ezh2 was found to specifically enhance T-helper (Th)1 and Th2 cell differentiation and plasticity. Ezh2 directly bound and facilitated correct expression of Tbx21 and Gata3 in differentiating Th1 and Th2 cells, accompanied by substantial tri-methylation at lysine 27 of histone 3 (H3K27-Me3). In addition, Ezh2 deficiency resulted in spontaneous generation of discrete IFN-γ and Th2 cytokine-producing populations in non-polarizing cultures, and under these conditions IFN-γ expression was largely dependent on enhanced expression of the transcription factor Eomesodermin. In vivo, Loss of Ezh2 caused increased pathology in a model of allergic asthma and resulted in progressive accumulation of memory phenotype Th2 cells. This study establishes a functional link between Ezh2 and transcriptional regulation of lineage-specifying genes in terminally differentiated CD4 T cells. Examination of Ezh2 binding in Th1 and Th2 cells.
2013-09-24 | E-GEOD-51079 | biostudies-arrayexpress
Project description:Phenotypic plasticity shapes genome architecture in the honeybee Apis mellifera
| PRJNA493569 | ENA
Project description:Microbial communities respond to temperature with physiological adaptation and compositional turnover. Whether thermal selection of enzymes explains marine microbiome plasticity in response to temperature remains unresolved. By quantifying the thermal behaviour of seven functionally-independent enzyme classes (esterase, extradiol dioxygenase, phosphatase, beta-galactosidase, nuclease, transaminase, and aldo-keto reductase) in native proteomes of marine sediment microbiomes from the Irish Sea to the southern Red Sea, we record a significant effect of the mean annual temperature (MAT) on enzyme’s response (R2, 0.51–0.80, p < 0.01 in all cases). Activity and stability profiles of 228 esterases and 5 extradiol dioxygenases from sediment and seawater across 70 locations worldwide (latitude 62.2°S–16°N, MAT –1.4ºC–29.5ºC) validate this thermal pattern. Modelling the esterase phase transition temperature as a measure of structural flexibility, confirm the observed relationship with MAT. Furthermore, when considering temperature variability in sites with non-significantly different MATs, the broadest range of enzyme thermal behaviour and the highest growth plasticity of the enriched heterotrophic bacteria occur in samples with the widest annual thermal variability. These results indicate that temperature-driven enzyme selection shapes microbiome thermal plasticity and that thermal variability finely tunes such processes and should be considered alongside MAT in forecasting microbial community thermal response
2023-02-07 | PXD039714 | Pride
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:Breast cancer remains a leading cause of death among women, encompassing diverse molecular subtypes with distinct clinical outcomes. The HER2+ subtype is particularly aggressive, with many patients eventually developing resistance to HER2-targeted therapies, underscoring the urgent need for alternative treatment strategies. Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2, represses the expression of genetic programs crucial for differentiation, control of proliferation, and apoptosis through histone H3 lysine 27 trimethylation (H3K27me3). To investigate the role of EZH2 in HER2+ tumor progression, we crossed a genetically engineered mouse model (GEMM) of HER2-driven breast cancer with a conditional Ezh2 knockout strain. The results showed that Ezh2 is essential for accelerating tumor initiation and metastatic dissemination in HER2-driven breast cancer. Combined bulk and single cell RNA sequencing analyses revealed a significant downregulation of basal cell populations in the absence of Ezh2, characterized by the loss of Tp63 expression, and an upregulation of luminal progenitor cell populations, driven by crucial transcription factors such as Esr1, thereby driving luminal lineage commitment. Further, inhibition of EZH2 in vitro resulted in increased expression of ER in HER2+ human breast cancer cell lines and rendered them susceptible to tamoxifen. Altogether, these findings demonstrate that EZH2 dictates breast cancer plasticity through control of cellular identity and provides rationale for combining EZH2 inhibitors with endocrine therapies to improve outcomes in HER2+ breast cancer.
2025-10-28 | GSE303527 | GEO