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GSE41091
Mus musculus
9 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Histone H2A.Z inheritance during the cell cycle and its impact on promoter organization and dynamics.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
While it has been clearly established that well positioned H2A.Z-containing nucleosomes flank the nucleosome depleted region (NDR) at the transcriptional start site (TSS) of active mammalian genes 1,2, how this chromatin-based information is transmitted through the cell cycle is unknown. We show here that in trophoblast stem (TS) cells, the level of H2A.Z at promoters decreases during S phase coinciding with homotypic (H2A.Z/H2A.Z) nucleosomes flanking the TSS becoming heterotypic (H2A.Z/H2A). Surprisingly, these nucleosomes remain heterotypic at M phase. At the TSS, we identify an unstable heterotypic H2A.Z-containing nucleosome in G1 which, strikingly, is lost following DNA replication. These dynamic changes in H2A.Z at the TSS mirror a global expansion of the NDR at S and M which, unexpectedly, is unrelated to transcriptional activity. Coincident with the loss of H2A.Z at promoters, it is targeted to the centromere when mitosis begins.
Publication Title
Histone H2A.Z inheritance during the cell cycle and its impact on promoter organization and dynamics.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
Illumina HiSeq 2500
Description
Mapping the transcriptomes governed by TCER-1 and DAF-16 upon germline loss
Publication Title
DAF-16 and TCER-1 Facilitate Adaptation to Germline Loss by Restoring Lipid Homeostasis and Repressing Reproductive Physiology in C. elegans.
Sample Metadata Fields
Sex, Specimen part, Disease, Cell line
View Samples- Homo sapiens
- 30 Downloadable Samples
- IlluminaHiSeq2000
Description
The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of novel therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus Kinase (JAK) activity with no precedent in adipose tissue biology that permanently confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells. Our findings highlight a novel role for the JAK/STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity. Overall design: Human pluripotent stem-cell derived mesenchymal progenitor cells (PSC-MPCs), white adipose cells (PSC-WA), and brown adipose cells (PSC-BA) were treated with DMSO (as control), a JAK3-inhibitor compound, and a SYK-inhibitor compound respectively. Transcriptomic expression profiling was performed at 24 hours and 7 days respectively. Three biological replicates are available for each condition defined by cell type, compound, and time.
Publication Title
White-to-brown metabolic conversion of human adipocytes by JAK inhibition.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-Hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2- hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D2-HG, we generated transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life spanrecapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant upregulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.
Publication Title
D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2500
Description
Elevated inflammation represents a hallmark of hematopoietic aging and leukemia development but mechanistically its impact on hematopoietic stem and progenitor cell (HSPC) maintenance remains incompletely understood. Here we identify Rad21/cohesin as a major component mediating inflammation-induced NF-kB signaling, which in turn limits self-renewal of HSPCs by induction of differentiation. Disruption of Rad21/cohesin diminishes inflammation-induced loss of self-renewal and induction of differentiation, but these effects are abrogated in NF-kB knockout (p50-/-) HSPCs. During aging, HSPCs exhibit an increased responsiveness to activate NF-kB signaling in response to inflammatory stimuli also resulting in activation of genes encoding for secreted cytokines. These cell intrinsic and extrinsic responses cooperatively enhance differentiation and loss of self-renewal of HSPCs resulting in increased selection of Rad21/cohesin deficient HSPCs exhibiting elevated self-renewal and myeloid skewed differentiation. Together, these results identify cohesin-mediated NF-kB signaling as a major axis connecting cell extrinsic increases in inflammation with the evolution of hallmark features HSC aging characterized by increases in self renewal and myeloid skewed differentiation aggravated by the concomitant selection of cohesin deficient HSPCs. Overall design: total samples: 12 (6 in vivo: 3 Rad21 knockdown, 3 control; 6 in vitro: 3 Rad21 knockdown, 3 control)
Publication Title
Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 38 Downloadable Samples
- IlluminaHiSeq2000
Description
Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3' untranslated region (3' UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx+ regions, which form a long stem–loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3' UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-? and tumor-necrosis-factor-a induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases. Overall design: 1) Evaluation of transcriptome expression and RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in poly(A) RNA-seq data derived from endothelial cell transcriptome after ADAR1 or ADAR2 knockdown (n=2 biological replicates per condition, total n=8 biological samples). 2) Evaluation of transcriptome expression and RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in total-RNA-seq data derived from peripheral blood mononuclear cells (n=12 total biological samples; n=4 replicates per condition). 3) Evaluation of transcriptome expression and RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in total-RNA-seq data derived from endothelial cell transcriptome under basal and hypoxic conditions (n=2 biological replicates per condition, total n=4 biological samples). 4) Evaluation of RNA editing sites (A-to-G and T-to-C nucleotide mismatches) in total RNA-seq data derived from endothelial cell transcriptome under basal and hypoxic conditions after ADAR1 knockdown (n=3 replicates per condition, total n=12 biological samples). 5) HuR iCLIP RNA-sequencing data derived from HUVEC HuR iCLIP after ADAR1 knockdown (scrambled control and siADAR1, n=1 per condition, total n=2 biological samples).
Publication Title
Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation.
Sample Metadata Fields
No sample metadata fields
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