Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA374657 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5252840_1.fastq.gz | Fastqsanger.gz | |||
| SRR5252840_2.fastq.gz | Fastqsanger.gz | |||
| SRR5252850_1.fastq.gz | Fastqsanger.gz | |||
| SRR5252850_2.fastq.gz | Fastqsanger.gz | |||
| SRR5252860_1.fastq.gz | Fastqsanger.gz |
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Project description:The presence of the PTPN22 risk variant (1858T) is associated to several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk variant on T cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve CD4+ T cells carrying two PTPN22 risk alleles overexpress a limited number of genes including CFLAR and 4-1BB important for cytotoxic T cell differentiation. Moreover, an increased number of cytotoxic EOMES+ CD4+ T cells were observed in PTPN22 risk allele carriers, which negatively correlated with a decreased number of naïve T cells in older individuals. No difference in the frequency of other CD4+ T cell subsets (Th1, Th17, Tfh, Treg) was observed in PTPN22 risk allele carriers and Treg suppressive capacity was not altered. Finally, in synovial fluids of RA patients, an accumulation of EOMES+ CD4+ T cells was observed with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, our data provide a novel mechanism of action of PTPN22 risk variant on CD4+ T-cell differentiation and identify EOMES+ CD4+ T cell as a relevant T cell subset in RA.
2018-02-27 | GSE94859 | GEO
Project description:Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene segregates with most autoimmune diseases; its risk allele encodes overactive PTPN22 phosphatases that alter B cell receptor (BCR) signaling potentially involved in the regulation of central B cell tolerance. To assess whether PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s). We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier control donors. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection, suggesting that early B cell tolerance checkpoint defects precede the onset of autoimmunity. In addition, gene array experiments comparing mature naïve B cells from healthy individuals carrying or not PTPN22 risk allele(s) revealed that the strength of association of PTPN22 for autoimmunity, second in importance only to the MHC, may not only be due to BCR signaling alteration but also to the regulation of other genes, which themselves have also been identified as involved in the development of autoimmune diseases. The PTPN22 risk allele is a single nucleotide change (cytidine to thymidine) at residue 1858, which results in a single amino acid substitution from arginine to tryptophan at position 620 of the PTPN22/Lyp protein.
2010-10-16 | GSE24736 | GEO
Project description:Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene segregates with most autoimmune diseases; its risk allele encodes overactive PTPN22 phosphatases that alter B cell receptor (BCR) signaling potentially involved in the regulation of central B cell tolerance. To assess whether PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s). We found that new emigrant/transitional and mature naive B cells from PTPN22 risk allele carriers contained high frequencies of autoreactive clones compared to non-carrier control donors. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection, suggesting that early B cell tolerance checkpoint defects precede the onset of autoimmunity. In addition, gene array experiments comparing mature naïve B cells from healthy individuals carrying or not PTPN22 risk allele(s) revealed that the strength of association of PTPN22 for autoimmunity, second in importance only to the MHC, may not only be due to BCR signaling alteration but also to the regulation of other genes, which themselves have also been identified as involved in the development of autoimmune diseases. The PTPN22 risk allele is a single nucleotide change (cytidine to thymidine) at residue 1858, which results in a single amino acid substitution from arginine to tryptophan at position 620 of the PTPN22/Lyp protein. Data from mature naïve B cell populations from patients carrying 1 or 2 PTPN22 T alleles and non-carrier patients were compared in order to characterize the impact of PTPN22 polymorphism on B cell physiology. RNA was extracted from batch-sorted CD19+CD10-CD21+CD27- conventional mature naive B cells using the Absolutely RNA microprep kit (Stratagene). 100-200 ng of RNA was obtained per sample, and the quality of the purified RNA was assessed by the Bioanalyzer from Agilent. Using the Ovation biotin system kit from Nugen, 30-50ng of RNA was amplified and labeled to produce cDNA. Labeled cDNA was hybridized on chips containing the whole human genome (Human Genome U133 Plus 2.0 from Affymetrix).
2010-10-16 | E-GEOD-24736 | biostudies-arrayexpress
Project description:To gain mechanistic insights into how EOMES regulates CD4+ T-cell differentiation and function, we performed an RNA-seq analysis using Eomes-GFP reporter mice (Eomes+/GFP) to isolate GFP+ (EOMES+) and GFP- (EOMES-) CD4+ T-cells by FACS sorting. We also sequenced RNA from Eomes-deficient GFP+ and GFP- CD4+ T-cells isolated from EomesΔT/GFP knock-out mice, in which one Eomes allele is disrupted by GFP insertion and the DNA-binding domain of the other allele is deleted in T cells by Lck-driven Cre recombinase. Hence, we had two populations of GFP+ cells where the EOMES locus was transcribed, one with a transcriptionally active EOMES protein (Eomes+/GFP) and another one with no transcriptionally active EOMES (EomesΔT/GFP), plus the respective GFP-negative controls isolated from the same mice. A homogeneous population of EOMES-expressing CD4+ T cells were obtained by transferring naïve sorted CD25- CD45RBhigh CD4+ T-cells isolated from Eomes+/GFP reporter or EomesΔT/GFP knock-out donor animals into Rag2-/- mice. After three weeks of adoptive transfer GFP+ and GFP- CD4+ T-cell populations from these mice were FACS-sorted for transcriptome analysis by RNA sequencing.
2020-10-01 | GSE145145 | GEO
Project description:The tissue accumulation of T cells expressing the transcription factor Eomesodermin (Eomes) has been reported in several chronic inflammatory diseases, including multiple sclerosis. However, the mechanisms whereby Eomes controls this accumulation and strengthens inflammation remains ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. We demonstrate that Eomes is dispensable for the initial priming of CD4+ T cells but is required for long-term maintenance of CNS-infiltrating CD4+ T cells. Our transcriptomic studies reveal that the impact Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and function. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in both healthy donors and multiple sclerosis patients. CD4+ T cells expressing Eomes exhibit enhanced mitochondrial functions, which resulted in their increased capacity to survive upon prolonged in vitro stimulation. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death.
2023-12-23 | GSE247862 | GEO
Project description:The tissue accumulation of T cells expressing the transcription factor Eomesodermin (Eomes) has been reported in several chronic inflammatory diseases, including multiple sclerosis. However, the mechanisms whereby Eomes controls this accumulation and strengthens inflammation remains ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. We demonstrate that Eomes is dispensable for the initial priming of CD4+ T cells but is required for long-term maintenance of CNS-infiltrating CD4+ T cells. Our transcriptomic studies reveal that the impact Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and function. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in both healthy donors and multiple sclerosis patients. CD4+ T cells expressing Eomes exhibit enhanced mitochondrial functions, which resulted in their increased capacity to survive upon prolonged in vitro stimulation. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death.
2023-12-23 | GSE247861 | GEO
Project description:The tissue accumulation of T cells expressing the transcription factor Eomesodermin (Eomes) has been reported in several chronic inflammatory diseases, including multiple sclerosis. However, the mechanisms whereby Eomes controls this accumulation and strengthens inflammation remains ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. We demonstrate that Eomes is dispensable for the initial priming of CD4+ T cells but is required for long-term maintenance of CNS-infiltrating CD4+ T cells. Our transcriptomic studies reveal that the impact Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and function. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in both healthy donors and multiple sclerosis patients. CD4+ T cells expressing Eomes exhibit enhanced mitochondrial functions, which resulted in their increased capacity to survive upon prolonged in vitro stimulation. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death.
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Project description:The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer's disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared to the common APOE3 allele. Using single-nuclei RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype-dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and myelination-related pathways, preserving synapses and myelination at the protein level. Conversely, these pathways were downregulated in APOE3 homozygotes, resulting in reduced synaptic and myelination proteins. In APOE4 carriers, excitatory neurons displayed reduced synaptic pathways similar to APOE3, but oligodendrocytes showed upregulated myelination pathways like APOE2. However, their synaptic and myelination protein levels remained unchanged or increased. APOE4 carriers also showed increased pro-inflammatory signatures in microglia but reduced responses to amyloid-β pathology. These findings reveal APOE genotype-specific molecular alterations in AD across cell types.
2025-03-17 | GSE237718 | GEO
Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.
2012-11-03 | E-GEOD-42002 | biostudies-arrayexpress
Project description:We correlated comprehensive T cell phenotyping data from peripheral blood to the corresponding genotype of different disease-associated and T cell related SNPs. This revealed significantly increased frequencies of naive CD4+ T cells (CD4+ TN) and T helper 17 (TH17) cells in carriers of intergenic SNP rs56258221 (BACH2/MIR4464) as compared to non-carriers. Functional experiments identified CD4+ TN from SNP-carriers to rather polarize towards pro-inflammatory subsets than into regulatory T cells (TREG). *** Due to data privacy concerns fastq files have not been uploaded ***
2024-04-22 | E-MTAB-14013 | biostudies-arrayexpress