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GSE73125
Mus musculus
81 Downloadable Samples
Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
Recent studies have shown that tissue macrophages (MF) arise from embryonic progenitors of the yolk sac (YS) and fetal liver and colonize the tissues before birth. Further studies have proposed that developmentally distinct tissue MF can be identified based on the differential expression of F4/80 and CD11b, but whether a characteristic transcriptional profile exists is largely unknown. Here, we established an inducible fate mapping system that facilitated the identification of A2 progenitors of the YS as source of F4/80hi but not CD11bhi MF. Large-scale transcriptional profiling of MF precursors from the YS until adulthood allowed the description of a complex MF pedigree. We further identified a distinct molecular signature of F4/80hi and CD11bhi MF and found that Irf8 was vital for MF maturation and the innate immune response. Our data provide new cellular and molecular insights into the origin and developmental pathways of tissue MF.
Publication Title
Transcriptome-based profiling of yolk sac-derived macrophages reveals a role for Irf8 in macrophage maturation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 36 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called microgliopathies. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS.
Publication Title
USP18 lack in microglia causes destructive interferonopathy of the mouse brain.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called microgliopathies. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS.
Publication Title
USP18 lack in microglia causes destructive interferonopathy of the mouse brain.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 1 Downloadable Sample
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
USP18 lack in microglia causes destructive interferonopathy of the mouse brain.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Gene expression profile of cancer cell lines of breast, lung, pancreatic, gasctric, ovarian, hepatocellular, prostate carcinomas and melanomas.
Publication Title
Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 46 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Postmenopausal hormone therapy (HT) is associated with many diseases and conditions, but the underlying molecular mechanisms involved are incompletely understood. The aim of the current study was to investigate the effect of 4 types of HT on gene transcription. 24 women (6 women in 4 treatment groups) received 2 mg 17-estradiol combined with 1 mg noresthisterone acetate (NETA), 1 mg 17-estradiol combined with 0.5 mg NETA, tibolone, or raloxifene hydrochloride. RNA was isolated from whole blood before treatment (baseline) and after 6 weeks on treatment. The changes in mRNA from baseline to 6 weeks were assessed with a microarray chip.
Publication Title
A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Human bone marrow is a complex, diversified and well-organized hematopoietic network changing composition with age. The purpose of this study was to analyze variations in relative precursor B cell abundance in bone marrow with age by means of global gene expression profiling. RNA was isolated from composite bone marrow from 25 healthy children, adolescents and adults age 2 months to 28 years. As reference transcript for precursor B cells we used recombination activating gene RAG1 exploring the data for other transcripts showing the same profile as RAG1 with age. We identified 54 genes with correlated expression profiles to RAG1 (r 0.9, p = 0), characterized by high expression at 3 - 20 months followed by a fast decline to lower signal levels maintained until early adulthood. Immunophenotyping from a similar healthy age-matched cohort (n = 37) showed a comparable decrease of precursor B cells. Of the 54 genes 15 were characteristically B cell associated representing cell surface molecules (CD19, CD72, CD79A, CD79B, CD180, IGL@, IGLL1, VPREB1, VPREB3), a signal transduction molecule (BLNK) and transcription factors (DNTT, EBF1, PAX5, POU2AF1, RAG2). Of the remaining transcripts some may represent novel B cell transcripts or genes involved in control of B cells.
Publication Title
Striking decrease in the total precursor B-cell compartment during early childhood as evidenced by flow cytometry and gene expression changes.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
In order to understand differentially regulated gene expression after the different treatments, 4 size matched tumors of each group were analyzed by microarrays.
Publication Title
Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 52 Downloadable Samples
Illumina HiSeq 2500
Description
NOTCH1 is mutationally activated in ~15% of cases of chronic lymphocytic leukaemia (CLL), but its role in B-cell development and leukemogenesis is not known. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ~50% of peripheral blood CLL cases lacking gene mutations. We identify a ‘NOTCH1 CLL gene expression signature’ in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival and signal transduction physiology. In particular, we show that MYC is a direct target of NOTCH1 via B-cell specific distal regulatory elements, thus implicating this oncogene in the pathogenesis of the disease. Overall design: RNA-Seq analysis
Publication Title
Common nonmutational <i>NOTCH1</i> activation in chronic lymphocytic leukemia.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 40 Downloadable Samples
- IlluminaHiSeq2500
Description
Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor post-infusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK cell functions following cytokine withdrawal to model post-infusion performance. In contrasts to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided functional advantages. Genome-wide analysis of cytosolic and polysome-associated mRNA revealed cytokine dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mTOR signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced functional advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15 stimulated NK cells was also observed using a clinically applicable protocol for NK cell expansion. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK cell cancer therapy. Overall design: Freshly isolated NK cells from 6 donors were activated with IL-2 or IL-15 for 48 hours, followed by cytokine withdrawal for 24 hours, resulting in four RNA samples per donor. From each sample, both the cytosolic as well as the polysomal fraction were collected. Donor 3 contains activation and post withdrawal data from two different donors due to poor RNA-quality obtained for some samples which did not allow for processing of the complete set of 6 donors (resulting in a total of 40 samples).
Publication Title
IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells.
Sample Metadata Fields
No sample metadata fields
View Samples