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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

ABSTRACT: IL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in susceptibility to autoimmune conditions. IL7R mRNA is induced in stimulated monocytes in a genetically determined manner. The aim this experiment was i) to characterise changes in gene expression with LPS, and ii) post-LPS stimulation, when IL7R is induced, ascertain if exposure to exogenous IL-7 elicits further changes in gene expression. The files form the raw data for a pairwise analysis and consist of monocytes from 8 individuals in 3 different states: Untreated (incubator control), 24h LPS, 24h LPS +2h IL-7 as detailed in the associated manuscript.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Homo sapiens

SUBMITTER: Hussein Al-Mossawi

PROVIDER: E-MTAB-8225 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

Project description:IL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in autoimmune pathogenesis. IL7R mRNA is induced in stimulated monocytes in a genetically determined manner. Here we show monocyte surface and soluble IL7R (sIL7R) protein are markedly expressed in response to lipopolysaccharide (LPS). Flow cytometry of synovial fluid-derived monocytes from patients with spondyloarthritis showed an enlarged subset of IL7R+ monocytes. Single-cell RNA sequencing of ex-vivo derived monocytes from the synovial fluid and blood of patients revealed that IL7R+ monocytes at the inflammatory site have a unique transcriptional profile that markedly overlaps that induced by IL-7 in-vitro and shows similarity to the previously described ‘Mono4’ subset. These data demonstrate disease-associated genetic variants at IL7R specifically impact monocyte surface IL7R and sIL7R following innate immune stimulation, suggesting a previously unappreciated key role for monocytes in IL-7 pathway biology and IL7R-associated diseases.

2019-08-12 | E-MTAB-8207 | biostudies-arrayexpress

Genetics of gene expression in primary immune cells

Project description:Gene expression arrays and genotyping data in primary human immune cells from healthy European 288 individuals.

2012-03-01 | E-MTAB-945 | biostudies-arrayexpress

Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection

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2022-10-11 | PXD036590 | Pride

IL7R mutational activation can initiate Ph-like and PAX5 P80R precursor B-cell acute lymphoblastic leukemia

Project description:Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemia stage in which B-cell precursors display self-renewal ability, initiating precursor B-ALL that resembles PAX5 P80R or Ph-like human leukemia. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving both JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are novel treatment avenues for IL-7R-related cases. Our model, a unique resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

2021-11-02 | PXD017147 | Pride

Transcription profiling by array of human prostate from patients with a previous diagnosis of Prostatic Intraepithelial Neoplasia and following consumption of high glucosinolate broccoli or peas to investigate interactions with the GSTM1 genotype

Project description:Twenty-two male volunteers aged 30-70 years with a previous diagnosis of Prostatic Intraepithelial Neoplasia (PIN) were recruited by a consultant urologist at Norfolk and Norwich University Hospital NHS Trust. Ethical approval for the trial was obtained from the Norfolk Research Ethics Committee (reference 05/Q0101/9). All participants gave written, informed consent. Volunteers were excluded if they were undergoing chemopreventive therapy, were receiving testosterone replacement medication, had active infection requiring treatment, a BMI <18.5 or >35 or were diagnosed with diabetes. Subjects were allocated into a 12-month, parallel dietary intervention trial consisting of two dietary intervention groups (i) consuming 400g high glucosinolate broccoli per week or (ii) consuming 400g peas per week. Volunteers avoided foods known to contain glucosinolates for 48 hours prior to each biopsy appointment to avoid acute effects. Needle biopsy samples (4 cores) of prostate tissue were obtained by Trans Rectal Ultrasound (TRUS) guided endoscopy at baseline, six and 12 months after the start of the dietary interventions. Additionally, benign and malignant (Gleason score 7-10) tissue samples obtained by Trans Urethral Resection of the Prostate (TURP) were provided from the Partners in Cancer Research Human Tissue Bank at the Norfolk and Norwich University Hospital NHS Trust.

2008-07-16 | E-MEXP-1243 | biostudies-arrayexpress

Liver transcriptome of biopsy-proven NAFLD patients at different stages of the disease

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2021-04-14 | E-MTAB-9815 | biostudies-arrayexpress

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| EGAD00001004584 | EGA

Overexpression of wild type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma

Project description:Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of T-ALL patients display very high IL7R mRNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, on leukemogenesis remains unclear. Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knock-in mice drives thymus hyperplasia due to increased proliferation of T-cell precursors, which subsequently infiltrate lymph nodes, spleen and bone marrow, ultimately leading to fatal leukemia. The tumors mimic key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of PI3K/Akt pathway that is paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing JAK/STAT, PI3K/Akt/mTOR and Notch signaling activation. Notably, we also find that established tumors no longer require high levels of IL-7R expression upon secondary transplantation and can progress even in the absence of IL-7, but remain sensitive to the Bcl-2 inhibitor Venetoclax. The relevance of these findings for human disease are highlighted by the fact that T-ALL patient samples with high wild type IL7R expression display a transcriptional signature resembling that from IL-7-stimulated pro-T cells and, critically, from IL7R mutant T-ALL cases. Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.

2021-09-07 | GSE128212 | GEO

Network analysis of the CSF proteome characterises convergent pathways of cellular dysfunction in ALS

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2021-03-16 | PXD024219 | Pride

Dexamethasone treatment of 3B4.15 T hybridoma cells

Project description:Investigation of whole genome gene expression level changes in Mus musculus 3B4.15 T hybridoma cells treated with 1microMolar Dexamethasone compared to mock treated cells. Interleukin-7 receptor alpha (IL-7Rα) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7Rα expression with diverse roles in T cell biology. Here we identify the transcriptional repressor, Growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7Rα upregulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7Rα upregulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7Rα transcription is upregulated in the absence of Gfi1 and downregulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8+, and not CD4+ T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo. A six chip study using total RNA recovered from three separate flasks of mock treated 3B4.15 cells and three separate flasks of Dexamethasone treated 3B4.15 cells . Each chip measures the expression level of 44170 target genes

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