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GSE43517
Mus musculus
4 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Ubiquitylation plays an important role in the control of Na+ homeostasis by the kidney. It is well established that the epithelial Na+ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney, and is also a circadian output gene. In heterologous expression systems USP2-45 binds to ENaC, deubiquitylates it and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na+ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that the USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences to wild-type littermates with respect to the diurnal control of Na+ or K+ urinary excretion and plasma levels neither on standard diet, nor after acute and chronic changes to low and high Na+ diets, respectively. Moreover, they had similar aldosterone levels either at low or high Na+ diet. Blood pressure measurements using telemetry did not reveal variations as compared to control mice. Usp2-KO did neither display alternations in ENaC or Na+,Cl--cotransporter (NCC) expression, nor were there any changes in regulatory protein levels, as evidenced by immunoblotting and transcriptome analysis. We conclude that USP2-45 is not crucial for the regulation of Na+ balance or maintenance of blood pressure in vivo.
Publication Title
Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Snail1 is a master factor of epithelial to mesenchymal transitioin (EMT), however, its role in embryonic vascular development is largely undefined. We used microarrays to compare the global programme of gene expression between cultured WT and Snai1 KO embyronic ECs.
Publication Title
A Snail1/Notch1 signalling axis controls embryonic vascular development.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Human T-cell Acute lymphoblastic Leukemia cell line CEM was transfected with either shRNA against ZMIZ1 or scrambled shRNA. Four (non-paired) biological replicates of each condition had mRNA assays performed using Affymetrix HG_U133_plus_2 arrays, with 54675 probe-sets. A supplementary Excel workbook holding the same processed data as the series matrix file is provided, with some probe set annotation, and a simple statistical comparison. The raw (.CEL) files are also provided.
Publication Title
Convergence of the ZMIZ1 and NOTCH1 pathways at C-MYC in acute T lymphoblastic leukemias.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 48 Downloadable Samples
Illumina HiSeq 2500
Description
Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 hours after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both, and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv vs. Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection, as GVHD severity was similar in recipients of wild-type Tconv combined with Notch-deprived vs. wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4+ Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and T helper polarization. In contrast, Notch inhibition dampened IFN-? and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with pathogenic effects of Notch in T cells at the earliest stages of GVHD. Overall design: 4 samples per cohort (Notch blockade using Dll1/4 neutralizing antibodies vs isotype control antibodies - GD) were analyzed. Additional 4 samples contained 4C T cells retrieved from syngeneic recipients.
Publication Title
Early Notch Signals Induce a Pathogenic Molecular Signature during Priming of Alloantigen-Specific Conventional CD4<sup>+</sup> T Cells in Graft-versus-Host Disease.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2500, Illumina HiSeq 2000
Description
The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question we performed transcriptomic analysis in mice with inducible and conditional ablation of the circadian clock system in the renal tubular cells (Bmal1lox/lox/Pax8-rtTA/LC1 mice). Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport. In parallel, kidneys from Bmal1lox/lox/Pax8-rtTA/LC1 mice exhibited a significant decrease in the NAD+/NADH ratio suggesting an increased anaerobic glycolysis and/or decreased mitochondrial function. In-depth analysis of two selected pathways revealed (i) a significant increase in plasma urea levels correlating with increased renal arginase 2 (Arg2) activity, hyperargininemia and increase of the kidney arginine content; (ii) a significantly increased plasma creatinine concentration and reduced capacity of the kidney to secrete anionic drugs (furosemide), paralleled by a ~80% decrease in the expression levels of organic anion transporter OAT3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at both the intra-renal and systemic levels and are involved in drug disposition. Overall design: Mice with a specific ablation of the Arntl gene encoding BMAL1 in the renal tubular cells were compared to wild-type littermate at ZT4 and ZT16 (ZT – Zeitgeber time units; ZT0 is the time of light on and ZT12 is the time of light off).
Publication Title
Nephron-Specific Deletion of Circadian Clock Gene Bmal1 Alters the Plasma and Renal Metabolome and Impairs Drug Disposition.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarrays to compared gene expression profilings in various tumors of the kidney.
Publication Title
Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2000
Description
The most recurrently mutated oncogene in T-cell acute lymphoblastic leukemia (T-ALL) is NOTCH1. The core Notch complex consists of an ICN protein, a Maml cofactor, and the DNA binding factor Rbpj. The known direct cofactors of Notch appear to act nonselectively, homogeneously driving Notch gene expression functions. It is unclear whether there are direct cofactors of Notch that act selectively and heterogeneously regulate ICN. We discovered that Zmiz1, a Protein Inhibitor of Activated STAT (PIAS)-like coactivator, directly bound ICN1. ChIP-Seq showed that Zmiz1 selectively co-bound only a subset of Notch-regulated enhancers. This led to hypothesize that Zmiz1 regulates only a subset of Notch1 target genes. To investigate this, we performed RNA-Seq on four 8946 cell linesin which L1601P (activated Notch1) or Zmiz1 were expressed alone or in combination. Zmiz1 induced ~10% of Notch target genes. The Notch target gene that was most strongly induced by Zmiz1 was Myc. Our data suggest that Zmiz1 selectively amplifies a subset of Notch target genes with strong amplification of Myc. Overall design: RNA-Seq in a murine T-ALL cell line
Publication Title
The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
We generated gene expression profiles of N2 (wild type) and strain FAS43 (Histone H3.3 null worms containing knockout alleles of all genes with homology to human histone H3.3: his-69, his-70, his-71, his-72, his-74) at embryonic and first larval instar stages. Overall design: RNA was isolated from N2 and H3.3 null mixed-stage embryos and L1 larvae grown at 20°C using Trizol, in duplicates for all samples. RNA-seq libraries were prepared using the Illumina TruSeq protocol.
Publication Title
Differential Expression of Histone H3.3 Genes and Their Role in Modulating Temperature Stress Response in <i>Caenorhabditis elegans</i>.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U219 Array (hgu219)
Description
Chromosomal translocations affecting Mixed Lineage Leukemia (MLL) gene result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report development of novel, highly potent and orally bioavailable small molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, show their profound effects in MLL leukemia cells and substantial survival benefit in mice models of MLL leukemia. Finally, we demonstrate efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate for the first time that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.
Publication Title
Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 99 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
The 600kb BP4-BP5 16p11.2 CNV (copy number variant) is associated with neuroanatomical, neurocognitive and metabolic disorders. These recurrent rearrangements are associated with reciprocal phenotypes such as obesity and underweight, macro- and microcephaly, as well as autism spectrum disorder (ASD) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal CNVs in 16p11.2.
Publication Title
A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples