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GSE62868
Mus musculus
11 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a major site of T2D risk. In this study, microarray data collected from mouse islets were used to identify genes that are regulated by cytokines at levels consistent with the chronic low-grade inflammation observed in T2D. The most cytokine-sensitive genes were then examined for association of single nucleotide polymorphisms (SNPs) with acute insulin response to glucose (AIRg) measured in the Genetics UndeRlying DIAbetes in HispaNics (GUARDIAN) study. In GUARDIAN, there was evidence of association of AIRg with SNPs in ARAP3 (5q31.3), F13A1 (6p25.3), KLHL6 (3q27.1), NID1 (1q42.3), PAMR1 (11p13), RIPK2 (8q21.3), and STEAP4 (7q21.12). These data support the mouse islet microarray data in detection of seven novel genes with potential importance to islet dysfunction in T2D. To further assess each gene, murine islets were exposed for 48-hrs to the following stressors representing models of beta-cell failure: 20nM rotenone (oxidative stress), 100nM thapsigargin (ER stress), 10pg/ml IL-1B + 20pg/ml IL-6 (cytokines/low-grade inflammation), 28mM glucose (hyperglycemia), or 50uM palmitate + 100uM oleate + 50uM linoleate (lipotoxicity). RT-PCR revealed that F13a1 was downregulated 3.3-fold by cytokines (P<0.05) and 2.6-fold by rotenone (P<0.05), Klhl6 was upregulated 4.3-fold by thapsigargin (P<0.01), Ripk2 was mildly (1.5-3-fold) but significantly upregulated by all stressors (P<0.05), and STEAP4 was profoundly cytokine-sensitive (167-fold upregulation, P<0.01). These findings reveal promising leads in elucidating islet dysfunction during the development of T2D.
Publication Title
An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 8 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip, Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
<i>APOL1</i> Renal-Risk Variants Induce Mitochondrial Dysfunction.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20), Illumina HumanHT-12 V4.0 expression beadchip
Description
To assess differential gene expression by APOL1 renal-risk (2 risk alleles) vs. non-risk (G0G0) genotypes in primary proximal tubule cells (PTCs), global gene expression (mRNA) levels were examined on Affymetrix HTA 2.0 arrays in primary PTCs cultured from non-diseased kidney in African Americans without CKD who underwent nephrectomy for localized renal cell carcinoma.
Publication Title
<i>APOL1</i> Renal-Risk Variants Induce Mitochondrial Dysfunction.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 1 Downloadable Sample
- Affymetrix Human Transcriptome Array 2.0 (hta20), Illumina HumanHT-12 V4.0 expression beadchip
Description
To elucidate pathways whereby apolipoprotein L1 gene (APOL1) G1 and G2 variants facilitate kidney disease in African Americans, human embryonic kidney cells (HEK293) were used to establish doxycycline-inducible (Tet-on) cell lines stably expressing reference APOL1 G0 and its G1 and G2 renal-risk variants. Illumina human HT-12-v4 arrays and Affymetrix HTA 2.0 arrays were employed to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics involved mitochondrial function; results were validated using immunoblotting, immunofluorescence and functional assays.
Publication Title
<i>APOL1</i> Renal-Risk Variants Induce Mitochondrial Dysfunction.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 12 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Puberty unmasks or accelerates nephropathies, including the nephropathy of diabetes mellitus (DM). A number of cellular systems implicated in the kidney disease of DM interweave, forming an interdependent functional web. We performed focused microarray analysis to test the hypothesis that one or more genes in the transforming growth factor beta (TGF-) signaling system would be differentially regulated in male rats depending on the age of onset of DM.
Publication Title
Prepubertal onset of diabetes prevents expression of renal cortical connective tissue growth factor.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 86 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Juvenile idiopathic arthritis (JIA) is the most common chronic childhood rheumatic disease in the Western world. To identify novel JIA predisposing loci, a genome-wide association study (GWAS) in 814 Caucasian JIA cases and 3058 Caucasian controls was completed. After adjusting for the most significant HLA associations, the strongest novel associations included rs6479891 (10q21, odds ratio (OR)=1.59, P=1.3x10-8) and rs10761747 (OR=1.34, P=4.0x10-5) within JMJD1C; rs12719740 (15q26, OR=1.47, P=3.3x10-7) near FAM169B; rs4688011 (3q13, OR=1.33, P=1.1x10-4) within C3orf1 and rs4254850 (4q31, OR=0.85, P=7.8x10-3) near IL15. Eleven SNPs were genotyped in Caucasian replication cohorts (1744 cases, 7010 controls) and meta-analysis continued to provide evidence for association with three of the SNPs (rs6479891, P=4.3x10-5; rs12719740, P=5.2x10-4; rs4688011, P=3.6x10-7). Analysis of expression data from 68 JIA cases and 23 controls overlapping in the GWAS cohort1 and published lymphoblastoid cell lines (LCL)2 showed cis eQTL associations for JMJD1C SNPs (P=0.01 and P=1.6x10-6, respectively), and the C3orf1 SNP (P=5.7x10-6).
Publication Title
Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13.
Sample Metadata Fields
Sex, Specimen part, Disease, Disease stage, Race
View Samples- Mus musculus
- 8 Downloadable Samples
NextSeq 500
Description
The mammary gland is a highly dynamic organ that mainly develops during puberty. Based on morphology and proliferation analysis, mammary stem cells (MaSCs) are thought to be close to or reside in the terminal end buds (TEBs) during pubertal development. However, exclusive stem cell markers are lacking, and therefore the true identity of MaSCs, including their location, multiplicity, dynamics and fate during branching morphogenesis, has yet to be defined. To gain more insights into the molecular identity and heterogeneity of the MaSC pool, we performed single cell transcriptome sequencing of mammary epithelial cells micro-dissected from ducts and TEBs during puberty. These data show that the behaviour of MaSCs cannot be directly linked to a single expression profile. Instead, morphogenesis of the mammary epithelium relies upon a heterogeneous population of MaSCs that functions long-term as a single equipotent pool of stem cells. Overall design: Ducts and terminal end buds were micro-dissected from the 4th and the 5th murine mammary gland at 5 weeks-of-age, dissociated into single cells, and FACS sorted. Single-cell transcriptomics was performed on live cells using an automated version of CEL-seq2 on live, FACS sorted cells. The StemID algorithm was used to identify clusters of cells corresponding to basal and luminal cells types derived from ducts and terminal end buds.
Publication Title
Identity and dynamics of mammary stem cells during branching morphogenesis.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Progesterone promotes differentiation coupled to proliferation and pro-survival in the breast, but inhibits estrogen-driven growth in the reproductive tract and ovaries. Herein, it is demonstrated, using progesterone receptor (PR) isoform-specific ovarian cancer model systems, that PR-A and PR-B promote distinct gene expression profiles that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target-gene p21 (CDKN1A) are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15 (CDKN2B). Chromatin immunoprecipitation (ChIP) assays performed on PR-isoform specific cells demonstrated that while each isoform is recruited to the same PRE-containing region of the p21 promoter in response to progestin, only PR-B elicits active chromatin marks. Overexpression of constitutively active FOXO1 in PR-A-expressing cells conferred robust ligand-dependent upregulation of the PR-B target genes GZMA, IGFBP1, and p21, and induced cellular senescence. In the presence of endogenous active FOXO1, PR-A was phosphorylated on Ser294 and transactivated PR-B at PR-B target genes; these events were blocked by the FOXO1 inhibitor (AS1842856). PR isoform-specific regulation of the FOXO1/p21 axis recapitulated in human primary ovarian tumor explants treated with progestin; loss of progestin sensitivity correlated with high AKT activity.
Publication Title
Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming.
Sample Metadata Fields
Treatment, Time
View Samples- Homo sapiens
- 18 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Progesterone receptors (PRs) are critical context-dependent transcription factors required for normal uterine (PR-A) and mammary gland (PR-B) development. Progesterone is proliferative in the breast, where PR-target genes include paracrine factors that mediate mammary stem cell self-renewal. In the context of altered signal transduction that typifies breast tumorigenesis, dysregulated (i.e. hyper-phosphorylated) PRs likely contribute to tumor progression by promoting cancer cell pro-survival and proliferation. Notably, in breast cancer cells, progestin-bound PRs induce rapid MAPK activation leading to selective regulation of growth-promoting genes by phosphorylated PR species. Functional domains within PR that interact with c-Src and estrogen receptors (ER) have been identified as indirect routes to MAPK activation. Herein, we describe a common docking (CD) domain located within the PR-B N-terminus, a motif first described in MAPKs that facilitates direct interactions between MAPKs and MEK1 or MAPK-phosphatases (MKPs). Mutation of negatively-charged amino acids, previously determined to be critical for CD domain function in MAPKs, within PR-B (mCD PR) did not alter MEK-binding or progestin-induced rapid signaling (i.e. MAPK activation) and PR transcriptional activity as measured by PRE-luciferase (reporter) assays. Microarray gene-expression analysis revealed that endogenous genes regulated by wt PR, but not mCD PR, are involved in critical cellular pathways regulating growth, proliferation, survival, and cancer. mCD PR failed to undergo ligand-induced phosphorylation on Ser81, a ck2-dependent site required for progestin-regulation of select growth-promoting genes (BIRC3, HSD112, HbEGF). Progestin-induced PR Ser81 phosphorylation mapped to CD domain-dependent binding of PR-B to MKP3, but did not require phosphatase activity. Receptors containing either mutant CD domains (mCD PR) or point mutations of Ser81 (S79/81A PR) failed to upregulate STAT5 and Wnt1, key PR-target gene products that act as critical mediators of mammary stem cell expansion. Inhibition of JAK/STAT signaling blocked progestin-induced STAT5 and Wnt1 expression. ChIP assays demonstrated that wt, but not phospho-mutant (S79/81A), PR-B was co-recruited to a PRE-containing enhancer region of the Wnt1 gene along with MKP3, ck2 and STAT5. Our studies reveal a novel scaffolding action of MKP3 mediated by interaction with the PR CD domain and required for ck2-dependent PR Ser81 phosphorylation. Co-regulation of select target genes by phospho-Ser81 PR and phospho-STAT5 is likely a global mechanism required for the activation of growth promoting programs active during normal mammary gland development and relevant to mechanisms of breast cancer progression.
Publication Title
A Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
The progesterone receptor specific gene targets were investigated in ovarian and breast cancer cell lines where FOXO1 was found to be a primary factor that cooperates with PR to activate cellular senescence genes (including p21) specifically in ovarian cells.
Publication Title
Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming.
Sample Metadata Fields
Treatment, Time
View Samples