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GSE29929
Mus musculus
14 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK.
Publication Title
The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The placental microvasculature of the human fetus is essential for the efficient transfer of gases, nutrients and waste between the mother and fetus. Microvascular hypoplasia of the terminal villi is associated with the placental pathology observed in cases of severe Intra Uterine Growth Restriction (IUGR). We used novel methods to isolate a pure population of placental microvascular endothelial cells from control preterm placentas (n=3) and placenta complicated by severe IUGR (n=6) with superimposed preeclampsia (n=5). Distal placental villous tissue was collected to enrich for terminal villi. Tissue was minced, digested and placental microvascular endothelial cells (PlMEC) were positively selected using tocosylated magnetic Dynabeads labeled with Human Endothelial Antigen lectin. The purity of the PlMEC (95%) was assessed by CD31 immunocytochemistry. RNA was extracted from the PlMEC samples and also from 3 term placenta and subjected to Affymetrix microarray analysis (U133Plus2 array chips). Data from the 3 term placentas and 3 preterm PlMEC arrays was used to generate an endothelial cell specific gene profile. This profile was used to identify the endothelial genes differentially regulated in all 6 IUGR cases. BTNL9 and NTRK2 transcripts were upregulated and SAA1, GNAS and SLAMF1 transcripts were downregulated as relative to the preterm controls. These changes were validated by Real time PCR in the PlMEC samples. This novel study is the first to identify endothelial candidate genes that may play a role in the villous hypoplasia of severe IUGR. This work advances our understanding of the molecular defects in placental microvascular endothelial cells in normal and pathologic pregnancies.
Publication Title
A distinct microvascular endothelial gene expression profile in severe IUGR placentas.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Tumor associated macrophages are contributing to local invasion, angiogensis, and metastasis during the progression of many kinds of tumor including glioma
Publication Title
Oligodendrocyte progenitor cells promote neovascularization in glioma by disrupting the blood-brain barrier.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 5 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To assess gene expression changes in Irgm1 (Lrg-47) deficient HSCs
Publication Title
Irgm1 protects hematopoietic stem cells by negative regulation of IFN signaling.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Hematopoietic stem cells (HSC) continuously regenerate a complete hematologic and immune system. Very few genes that regulate this process have yet been identified. In order to identify factors governing differentiation, we have compared the transcriptome of highly purified HSC with their differentiated progeny, including erythrocytes, granulocytes, monocytes, NK cells, activated and nave T-cells, and B-cells. Chromosomal analysis revealed that HSC were more transcriptionally active than other cell types across most chromosomes. Each lineage expressed ~100 to 400 genes uniquely, including many previously uncharacterized genes. Overexpression of two fingerprint genes resulted in a significant bias in differentiation indicating a role in cell fate determination, demonstrating the utility of these data for modulation of specific cell types.
Publication Title
Hematopoietic fingerprints: an expression database of stem cells and their progeny.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 21 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background: Identifying individuals at heightened cardiovascular risk is a priority for reducing the global burden of cardiovascular disease. Aspirin is widely used to prevent cardiovascular events, though with variable results. Therefore, we hypothesized that aspirin exposure would reveal novel biological pathways relevant to the development of cardiovascular events. Methods: We administered aspirin, followed by peripheral blood RNA microarray profiling, in a discovery cohort of healthy volunteers (n = 50, HV1), followed by two validation cohorts of healthy volunteers (n = 53, HV2) or outpatient cardiology (OPC, n = 25) patients, in conjunction with platelet function testing with the platelet functions score (PFS, HV1 and HV2) or the VerifyNow Asprin (VN, OPC) test. Sets of coexpressed genes, or Factors were identified via Bayesian sparse factor analysis and associated with platelet function in HV1 and validated in HV2 and OPC. Validated factors were associated with death/MI in observational (n = 191) and case:control (n = 447) patient cohorts with available RNA data collected at the time of cardiac catheterization. Results: Factor analysis yielded 20 Factors, of which one, Factor 14, contained 60 genes and was associated with PFS in HV1 (r = -0.31, p-value = 0.03). Factor 14 was associated with platelet function with the same strength and direction in HV2 (r = -0.34, p-value = 0.02) and OPC (one-sided p-value for aspirin resistant vs. aspirin sensitive = 0.046), thus validating the association. Factor 14 was associated with death/MI in the two patient cohorts, odds ratio (OR) = 1.2, 95% CI [1.02-1.4], p-value = 0.01 and hazard ratio = 1.5, [1.2-1.9], p = 0.001, respectively, independent of known cardiovascular risk factors (combined OR = 1.2, CI = [1.02, 1.4], p = 0.03). Factor 14 and the expression of the Factor 14 transcript most highly correlative of PFS, ITGA2B, improved reclassification compared to traditional risk factors (category-free net reclassification index = 31% and 37%, p 0.0002 for both). Conclusions: By challenging humans subjects with aspirin, a medication used for cardiovascular risk reduction, we elucidated genes and pathways that may underlie platelet function and mechanisms responsible for cardiovascular death/MI.
Publication Title
Aspirin insensitive thrombophilia: transcript profiling of blood identifies platelet abnormalities and HLA restriction.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 18 Downloadable Samples
NextSeq 500
Description
In response to UVB irradiation, human keratinocytes transiently block cell cycle progression to allow ample time for DNA repair and cell fate determination. These cellular processes are important for evading the initiation of carcinogenesis in skin. We previously showed that repression of mRNA translation initiation through phosphorylation of eIF2a (eIF2a-P) protects keratinocytes from UVB-induced apoptosis. In this study, we elucidate the mechanism of eIF2a-P cytoprotection in response to UVB. Loss of eIF2a-P induced by UVB diminished G1 arrest, DNA repair rate, and cellular senescence coincident with enhanced cell death in human keratinocytes. Genome-wide translation analyses revealed that the mechanism for these critical changes directed by eIF2a-P involved induced expression of CDKN1A encoding p21 protein. p21 is a major regulator of the cell cycle, and we show that human CDKN1A mRNA splice variant 4 is preferentially translated by eIF2a-P during stress in a mechanism mediated in part by upstream ORFs situated in the 5'-leader of CDKN1A mRNA. We conclude that eIF2a-P is cytoprotective in response to UVB by a mechanism featuring translation of a specific splice variant of CDKN1A that facilitates G1 arrest and subsequent DNA repair. Overall design: Untreated and irradiated N-TERT keratinocytes are split into 3 groups: monosome fraction, polysome fraction, and whole cell lysate. N=3.
Publication Title
Translational control of a human <i>CDKN1A</i> mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 40 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 44 Downloadable Samples
- Illumina HiSeq 2000
Description
Gene expression profiling was carried out in six (wild type, ß2SP+/-, ß2SP-/-, SMAD3+/-, SMAD3-/- and ß2SP+/-/ SMAD3+/-) different mouse knockout embryonic fibroblast (MEF) cells. Beta-2-spectrin (ß2SP) is a dynamic intracellular non-pleckstrin homology (PH)-domain protein that belongs to a family of polypeptides that have been implicated in conferring cell polarity. Spectrins have been linked to multiple signaling pathways, including cell cycle regulation, DNA repair and TGFß signaling. In this study, we report a major role of the TGFß/Smad3 adaptor ß2-Spectrin in conserving genomic integrity from alcohol-induced DNA damage and describe a novel pathway that protects genomes from genotoxic stresses. To determine the mechanism for the oncogenic switch, and whether it is related to the role of ß2SP in TGF-ß signaling transduction or secondary to its cytoskeletal functions, we analyzed disruption of two elements of the TGF-ß pathway by generating double heterozygous Sptbn1+/-/Smad3+/- mice. Overall design: Whole-transcriptome RNA sequencing MEF cells of the following genotypes was carried out on an Illumina HiSeq 2000 sequencer: wildtype, heterozygous Beta-2-spectrin knockout (ß2SP+/-), homozygous Beta-2-spectrin knockout (ß2SP-/-), heterozygous SMAD3 (Mothers against decapentaplegic, Drosophila, Homolog of 3, SMAD3+/-), homozygous knockout SMAD3-/-, and double heterozygous mutation of Beta-2-spectrin and SMAD3 (ß2SP+/-/ SMAD3+/-).
Publication Title
TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 40 Downloadable Samples
- Illumina HiSeq 2000
Description
Gene expression profiling was carried out in two liver tumors and one normal liver isolated from ß2SP+/-; SMAD3+/- mice, and one normal liver isolated from wild type mouse. Whole-transcriptome sequencing of these 4 liver tissues. Overall design: Whole-transcriptome RNA sequencing of the 4 different samples
Publication Title
TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome.
Sample Metadata Fields
No sample metadata fields
View Samples