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GSE84000
Mus musculus
8 Downloadable Samples
Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions. F4/80-positive ATMs were isolated from obese vs lean mice. High-fat feeding of wild-type mice and myeloid-specific Hif1-/- mice was used to examine the role of hypoxia-inducible factor-1 (HIF-1) in ATMs part of obese adipose tissue. In vitro, bone marrow-derived macrophages were co-cultured with adipose tissue explants to examine adipose tissue-induced changes in macrophage phenotypes. Transcriptome analysis, real-time flux measurements, ELISA and several other approaches were used to determine the metabolic signatures and inflammatory status of macrophages. In addition, various metabolic routes were inhibited to determine their relevance for cytokine production. Transcriptome analysis and extracellular flux measurements of mouse ATMs revealed unique metabolic rewiring in obesity characterised by both increased glycolysis and oxidative phosphorylation. Similar metabolic activation of CD14+ cells in obese individuals was associated with diabetes outcome. These changes were not observed in peritoneal macrophages from obese vs lean mice and did not resemble metabolic rewiring in M1-primed macrophages. Instead, metabolic activation of macrophages was dose-dependently induced by a set of adipose tissue-derived factors that could not be reduced to leptin or lactate. Using metabolic inhibitors, we identified various metabolic routes, including fatty acid oxidation, glycolysis and glutaminolysis, that contributed to cytokine release by ATMs in lean adipose tissue. Glycolysis appeared to be the main contributor to the proinflammatory trait of macrophages in obese adipose tissue. HIF-1, a key regulator of glycolysis, nonetheless appeared to play no critical role in proinflammatory activation of ATMs during early stages of obesity. Our results reveal unique metabolic activation of ATMs in obesity that promotes inflammatory cytokine release. Further understanding of metabolic programming in ATMs will most likely lead to novel therapeutic targets to curtail inflammatory responses in obesity.
Publication Title
Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 39 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Atopic dermatitis (AD) is the most common inflammatory skin disease, with high unmet need for new therapies that are safe for chronic use. Emerging data suggest that TH2-cytokines play important roles in a variety of allergic and atopic conditions, including asthma and AD. In early phase clinical trials, dupilumab (a fully human monoclonal antibody against IL-4R that potently blocks IL-4 and IL-13 signaling) rapidly and markedly improved clinical measures in adults with either asthma (with elevated eosinophil counts) or moderate-to-severe AD. The pathomechanisms that may be impacted by IL-4/13 blockade in these disease settings have not yet been characterized in detail.
Publication Title
Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.
Sample Metadata Fields
Specimen part, Treatment, Subject, Time
View Samples- Homo sapiens
- 43 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Different allergens induce different immune responses
Publication Title
Molecular profiling of contact dermatitis skin identifies allergen-dependent differences in immune response.
Sample Metadata Fields
Sex, Subject
View Samples- Homo sapiens
- 105 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of TH2-, TH22-, and some TH17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures.
Publication Title
Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
Sample Metadata Fields
Sex, Age, Time
View Samples- Homo sapiens
- 10 Downloadable Samples
IlluminaHiSeq2000
Description
MicroRNA (miRNA) play a major role in the post-transcriptional regulation of gene expression. In mammals most miRNA derive from the introns of protein coding genes where they exist as hairpin structures in the primary gene transcript, synthesized by RNA polymerase II (Pol II). These are cleaved co-transcriptionally by the Microprocessor complex, comprising DGCR8 and the RNase III endonuclease Drosha, to release the precursor (pre-)miRNA hairpin, so generating both miRNA and spliced messenger RNA1-4. However, a substantial minority of miRNA originate from Pol II-synthesized long non coding (lnc) RNA where transcript processing is largely uncharacterized5. Here, we show that most lnc-pri-miRNA do not use the canonical cleavage and polyadenylation (CPA) transcription termination pathway6, but instead use Microprocessor cleavage both to release pre-miRNA and terminate transcription. We present a detailed characterization of one such lnc-pri-miRNA that generates the highly expressed liver-specific miR-1227. Genome-wide analysis then reveals that Microprocessor-mediated transcription termination is commonly used by lnc-pri-miRNA but not by protein coding miRNA genes. This identifies a fundamental difference between lncRNA and pre-mRNA processing. Remarkably, inactivation of the Microprocessor can lead to extensive transcriptional readthrough of lnc-pri-miRNA, resulting in inhibition of downstream genes by transcriptional interference. Consequently we define a novel RNase III-mediated, polyadenylation-independent mechanism of Pol II transcription termination in mammalian cells. Overall design: Chromatin associated RNA-seq from sicntrl,siDrosha,siDGCR8 treated Hela cells. Same for sicntrl and siDGCR8 from Huh7 cells. Nuclear polyA + and polyA- RNA-seq from sicntrl and siDGCR8 in HeLa cells. Chromatin associated RNA-seq from siDicer treated Hela cells.
Publication Title
Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 13 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Positional identification of variants of Adamts16 linked to inherited hypertension.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 7 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
We used Affymetrix GeneChips to expression profile rat kidney NRK-52E cells treated with control scrambled siRNA or siRNA specifically targeting Adamts16. The goal of this project was to identify the downstream genes regulated by Adamts16 (the function of Adamts16 has yet to be fully delineated). Gene expression differences resulting from these siRNA-mediated gene knockdown experiments will be compared to the gene expression profiling experiments comparing kidneys from Dahl salt-senstive hypertensive inbred strain versus less hypertensive S.LEW(D1MCO4x1x3Bx1) congenic strain. The S.LEW(D1MCO4x1x3Bx1) congenic animal is an S rat containing the LEWIS allele for Adamts16 instead of the S allele. Gene expression differences in the kidneys of S.LEW(D1MCO4x1x3Bx1) versus S are hypothesized to result from sequence differences between the S and LEWIS alleles for Adamts16. It is further hypothesized that allelic differences in Adamts16 in inbred rats is responsible for blood pressure variance. The downstream genes regulated by Adamts16 may provide insight pertaining to the mechanism of blood pressure differences.
Publication Title
Positional identification of variants of Adamts16 linked to inherited hypertension.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 6 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
We used Affymetrix GeneChips to expression profile kidneys from Dahl salt-senstive hypertensive inbred strain and less hypertensive S.LEW(D1MCO4x1x3Bx1) congenic strain to identify genes downstream of Adamts16 (the function of Adamts16 has yet to be fully delineated). The S.LEW(D1MCO4x1x3Bx1) congenic animal is an S rat containing the LEWIS allele for Adamts16 instead of the S allele. It is hypothesized that allelic differences in Adamts16 in inbred rats is responsible for blood pressure variance. We further hypothesize that gene expression differences in the kidneys of S.LEW(D1MCO4x1x3Bx1) versus S result from sequence differences between the S and LEWIS alleles of Adamts16. Lastly, the downstream genes differentially regulated by the Adamts16 alleles may provide insight pertaining to the mechanism of blood pressure differences. Gene expression differences resulting from these kidney comparisons will be compared to the gene expression profiling experiments comparing siRNA-mediated knockdown of Adamts16 in NRK-52E kidney cells versus scrambled siRNA control.
Publication Title
Positional identification of variants of Adamts16 linked to inherited hypertension.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 94 Downloadable Samples
- Illumina HiSeq 4000, Illumina HiSeq 2500
Description
Numerous long intervening non-coding RNA (lincRNA) are generated from the mammalian genome by RNA polymerase II (Pol II) transcription. Although multiple functions have been ascribed to lincRNA, their synthesis and turnover remain poorly characterised. Here we define systematic differences in transcription and RNA processing between protein-coding and lincRNA genes in human HeLa cells. This is based on a range of nascent transcriptomic approaches applied to different nuclear fractions, including mammalian native elongating transcript sequencing (mNET-seq). Notably mNET-seq patterns specific for different Pol II CTD phosphorylation states reveal weak co-transcriptional splicing and poly(A) signal independent Pol II termination on lincRNA as compared to pre-mRNA. In addition, lincRNA are mostly restricted to chromatin where they are co-transcriptionally degraded by the RNA exosome. We also show that a lincRNA specific co-transcriptional RNA cleavage mechanism acts to induce premature termination. In effect functional lincRNA must escape from this targeted nuclear surveillance process. Overall design: We employed CTD phospho specific mNET-Seq with pla-B splicing inhibitor and RNA processing factors knockdown (DGCR8, Dicer1, EXOSC3 and CPSF73 proteins). mNET-seq experiments with 1% Empigen detergent treatment were performed to separate Pol II-associated complex from Pol II. We also analyzed subcellur RNA and pA+ and pA- nucleoplasm RNA libraries for RNA processing efficiency and the turnover. There are 4 raw files come from an illumina experiment (per sample), produced in 2 lanes. They were all mapped together.
Publication Title
Distinctive Patterns of Transcription and RNA Processing for Human lincRNAs.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 47 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotypes, demonstrating that diet and genetic factors impact risk by distinct combinatorial mechanisms. We analyzed expression profiles of small intestine crypts and villi from mice with nutritional and genetic risk factors. The results advanced our understanding of the mechanistic roles played by major risk factors in the pathogenesis of intestinal tumors.
Publication Title
Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer.
Sample Metadata Fields
Age, Specimen part
View Samples