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GSE12147
Mus musculus
30 Downloadable Samples
Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
The nuclear receptor PPARalpha is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after acute and chronic treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the downregulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism; suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Taken together, these studies articulate the therapeutic promise of a selective PPARalpha agonist.
Publication Title
Molecular characterization of novel and selective peroxisome proliferator-activated receptor alpha agonists with robust hypolipidemic activity in vivo.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 12 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
Here we uncover antagonistic regulation of transcript levels in the germline of Caenorhabditis elegans hermaphrodites. The histone methyltransferase MES-4 marks genes expressed in the germline with methylated Lys36 on histone H3 (H3K36me) and promotes their transcription; MES-4 also represses genes normally expressed in somatic cells and genes on the X chromosomes. The DRM complex, which includes E2F/DP and Retinoblastoma homologs, affects germline gene expression and prevents excessive repression of X-chromosome genes. Using genome-scale analyses of germline tissue, we show that common germline-expressed genes are activated by MES-4 and repressed by DRM, and that MES-4 and DRM co-bind many germline-expressed genes. Reciprocally, MES-4 represses and DRM activates a set of autosomal soma-expressed genes and overall X-chromosome gene expression. Mutations in mes-4 or the DRM subunit lin-54 oppositely skew target transcript levels and cause sterility; a double mutant restores near wild-type transcript levels and germ cell development. Together, yin-yang regulation by MES-4 and DRM ensures transcript levels appropriate for germ cell function, elicits robust but not excessive dampening of X-chromosome-wide transcription, and may poise genes for future expression changes. Our study reveals that conserved transcriptional regulators implicated in development and cancer counteract each other to fine-tune transcript dosage.
Publication Title
Opposing activities of DRM and MES-4 tune gene expression and X-chromosome repression in Caenorhabditis elegans germ cells.
Sample Metadata Fields
Sex
View Samples- Caenorhabditis elegans
- 12 Downloadable Samples
- Affymetrix C. elegans Genome Array (celegans)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Chromosome-biased binding and gene regulation by the Caenorhabditis elegans DRM complex.
Sample Metadata Fields
Specimen part
View Samples- Caenorhabditis elegans
- 12 Downloadable Samples
Affymetrix C. elegans Genome Array (celegans)
Description
DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in development and cancer. Here we perform microarray expression profiling analysis of lin-54, a DNA-binding member of the DRM complex. To identify genes regulated by LIN-54 in soma and germline, we analyzed wild-type and lin-54 mutant C. elegans embryos and isolated germlines. We chose embryos because they consist primarily of somatic cells, at a developmental stage with both active cell divisions and dynamic developmental gene expression programs. Since lin-54 null animals are sterile, embryos were obtained from a strain carrying the partial loss-of-function allele lin-54(n2990). Germlines were dissected from lin-54(n3423) null adults that lack detectable transcript and protein. The results revealed conserved roles for DRM in regulating genes involved in cell division, development, and reproduction. We find LIN-54 promotes expression of reproduction genes in the germline, but prevents ectopic activation of germline-specific genes in embryonic soma. Strikingly, genomics and cytological analyses show that DRM binding, a DRM binding motif, and LIN-54-regulated genes are all autosome-enriched. One paradoxical exception occurs the germline, where DRM binds autosomes but genes down-regulated in DRM mutants are enriched on X chromosomes.
Publication Title
Chromosome-biased binding and gene regulation by the Caenorhabditis elegans DRM complex.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
IonTorrentProton
Description
We reported that NRP-1 expression on CD4+ T cells was probably induced by NRP-1 transfer from macrophages to T cells. In HER2+ BC, NRP-1 expressing TIIs correlated with better clinical outcomes. Overall design: Examination of monocytes and monocyte derived macrophages.
Publication Title
Downregulation of neuropilin-1 on macrophages modulates antibody-mediated tumoricidal activity.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 31 Downloadable Samples
- NextSeq 500
Description
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia. Overall design: mRNA sequencing of various immunophenotypic populations from KMT2A-MLLT3 xenograft leukemias with or without FLT3-N676K generated using Illumina NextSeq 500.
Publication Title
FLT3<sup>N676K</sup> drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
<Objective> To compare gene expression in labial salivary glands (LSG) of IgG4-related disease (IgG4-RD) with Sjgrens syndrome (SS).
Publication Title
DNA microarray analysis of labial salivary glands in IgG4-related disease: comparison with Sjögren's syndrome.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 40 Downloadable Samples
- NextSeq 500
Description
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3ITD, FLT3N676K, and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Subclonal FLT3N676K mutations also accelerate disease, possibly by providing stimulatory factors such as Mif. Acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 were identified in KMT2A-MLLT3 leukemia cells and favored clonal expansion. During clonal evolution, serial genetic changes at the KrasG12D locus was observed, consistent with a strong selective advantage of additional KrasG12D. KMT2A-MLLT3 leukemias with signaling mutations enforced Myc- and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlights the importance of activated signaling as a contributing driver in this disease. Overall design: mRNA sequencing of KMT2A-MLLT3 leukemias with or without activating mutations generated using Illumina NextSeq 500.
Publication Title
De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Saccharomyces cerevisiae
- 41 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Inferring causal metabolic signals that regulate the dynamic TORC1-dependent transcriptome.
Sample Metadata Fields
Treatment
View Samples- Saccharomyces cerevisiae
- 14 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
Dynamic mRNA gene expression from the wildtype YSBN6 during a nutritional downshift from glutamine to proline. Glutamine and proline were initially together in the media, with cells consuming exlusively glutamine (proline utilization inhibited due to nitrogen catabolite repression). The concentration of glutamine was frequently evaluated at-line, and the moment at which glutamine was not detected anymore is referred to as the time of the shift.
Publication Title
Inferring causal metabolic signals that regulate the dynamic TORC1-dependent transcriptome.
Sample Metadata Fields
Treatment
View Samples