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SRP047233
Homo sapiens
54 Downloadable Samples
IlluminaHiSeq2000
Description
Truncating mutations of CHD8, encoding a chromodomain helicase, and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA-seq) with genome-wide CHD8 binding (ChIP-seq). Suppressing CHD8 to levels comparable with loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8 binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (p = 1.01x10-9) and CHD8-bound genes (p = 4.34x10-3), which align with previously identified co-expression modules during fetal development. We also find an intriguing enrichment of cancer related gene-sets among CHD8-bound genes (p < 1.9x10-11). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis. Overall design: RNA-seq in NPCs treated with shRNAs targeting CHD8. For controls, NPCs were treated with shRNAs targeting GFP and LacZ. Infection and sequencing was carried out in two separate batches, with one GFP and one LacZ sample in each batch. All samples were sequenced in two technical replicates.
Publication Title
CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 19 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integration of transcript expression, copy number and LOH analysis of infiltrating ductal carcinoma of the breast.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 19 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Introduction: A major challenge in the interpretation of genomic profiling data generated from breast cancer samples is the identification of driver genes as distinct from bystander genes which do not impact tumorigenesis. One way to assess the relative importance of alterations in the transcriptome profile is to combine complementary analyses that assess changes in the copy number alterations (CNAs). This integrated analysis permits the identification of genes with altered expression that map within specific chromosomal regions that demonstrate copy number alterations, providing a mechanistic approach to identify the 'driver genes.
Publication Title
Integration of transcript expression, copy number and LOH analysis of infiltrating ductal carcinoma of the breast.
Sample Metadata Fields
Specimen part, Subject
View Samples- Rattus norvegicus
- 6 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
HIV Tg rats exhibit pulmonary hypertension and pulmonary artery remodeling. In an effort to begin to understand cell signaling pathways which are altered in lungs from HIV transgenic rats, we used microarray analysis.
Publication Title
Human immunodeficiency virus transgenic rats exhibit pulmonary hypertension.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 29 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Schizophrenia (SCZ) and bipolar disorder (BPD) are polygenic disorders with many genes contributing to their etiologies. The aim of this investigation was to search for dysregulated molecular and cellular pathways for these disorders as well as psychosis. We conducted a blood-based microarray investigation in two independent samples with SCZ and BPD from San Diego (SCZ=13, BPD=9, control=8) and Taiwan [data not included](SCZ=11, BPD=14, control=16). Diagnostic groups were compared to controls, and subjects with a history of psychosis [PSYCH(+): San Diego (n=6), Taiwan (n=14)] were compared to subjects without such history [PSYCH(-): San Diego (n=11), Taiwan (n=14)]. Analyses of covariance comparing mean expression levels on a gene-by-gene basis were conducted to generate the top 100 significantly dysregulated gene lists for both samples by each diagnostic group. Gene lists were imported into Ingenuity Pathway Analysis (IPA) software. Results showed the ubiquitin proteasome pathway (UPS) was listed in the top ten canonical pathways for BPD and psychosis diagnostic groups across both samples with a considerably low likelihood of a chance occurrence (p = .001). No overlap in dysregulated genes populating these pathways was observed between the two independent samples. Findings provide preliminary evidence of UPS dysregulation in BPD and psychosis as well as support further investigation of the UPS and other molecular and cellular pathways for potential biomarkers for SCZ, BPD, and/or psychosis.
Publication Title
Preliminary evidence of ubiquitin proteasome system dysregulation in schizophrenia and bipolar disorder: convergent pathway analysis findings from two independent samples.
Sample Metadata Fields
Sex, Age, Disease
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background: Zidovudine remains the cornerstone drug for prophylaxis to prevent mother-to-child HIV-1 transmission. A mild but long-lasting hematological multilineage defect is observed in children exposed in utero.
Publication Title
Genotoxic signature in cord blood cells of newborns exposed in utero to a Zidovudine-based antiretroviral combination.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 13 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
1,2-unsaturated pyrrolizidine alkaloids (PA) are plant metabolites predominantly occurring in the plant families Asteraceae and Boraginaceae. Acute and chronic PA poisoning causes severe hepatotoxicity. So far, the molecular mechanisms of PA toxicity are not well understood. To analyze its mode of action, primary human hepatocytes were exposed to a non-cytotoxic dose of 100 M of four structurally different PA: echimidine, heliotrine, senecionine, senkirkine. Changes in mRNA expression were analyzed by a whole genome microarray. Employing cut-off values with a |fold change| of 2 and a q-value of 0.01, data analysis revealed numerous changes in gene expression. In total, 4556, 1806, 3406 and 8623 genes were regulated by echimidine, heliotrine, senecione and senkirkine, respectively. 1304 genes were identified as commonly regulated. PA affected pathways related to cell cycle regulation, cell death and cancer development. The transcription factors TP53, MYC, NFB and NUPR1 were predicted to be activated upon PA treatment. Furthermore, gene expression data showed a considerable interference with lipid metabolism and bile acid flow. The associated transcription factors FXR, LXR, SREBF1/2, and PPAR// were predicted to be inhibited. In conclusion, though structurally different, all four PA significantly regulated a great number of genes in common. This proposes similar molecular mechanisms, although the extent seems to differ between the analyzed PA as reflected by the potential hepatotoxicity and individual PA structure.
Publication Title
Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Clariom S Human array (clariomshuman)
Description
HepG2 and THP-1 cells, the latter differentiated by phorbol 12-myristate 13-acetate (PMA), were co-cultured and characterized for typical liver-specific functions, such as xenobiotic detoxification, lipid and cholesterol metabolism. Furthermore, liver injury-associated pathways, such as inflammation, were studied. In general, the co-cultivation of these cells produced a pro-inflammatory system, as indicated by increased levels of cytokines (IL-8, TGF-α, IL-6, GM-CSF, G-CSF, TGF-β, and hFGF) in the respective supernatant. Increased expression levels of target genes of the aryl hydrocarbon receptor (AHR), e.g., CYP1A1, CYP1A2 and CYP1B1, were detected, accompanied by the increased enzyme activity of CYP1A1. Moreover, transcriptome analyses indicated a significant upregulation of cholesterol biosynthesis, which could be reduced to baseline levels by lovastatin. In contrast, total de novo lipid synthesis was reduced in co-cultured HepG2 cells. Key events of the adverse outcome pathway (AOP) for fibrosis were activated by the co-cultivation, however, no increase in the concentration of extracellular collagen was detected. This indicates, that AOP should be used with care. In summary, the indirect co-culture of HepG2/THP 1 cells results in an increased release of pro-inflammatory cytokines, an activation of the AHR pathway and an increased enzymatic CYP1A activity.
Publication Title
Indirect co-cultivation of HepG2 with differentiated THP-1 cells induces AHR signalling and release of pro-inflammatory cytokines.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Double-stranded RNA-binding proteins are key elements in the intracellular localization of mRNA and its local translation. Staufen is a double-stranded RNA binding protein involved in the localised translation of specific mRNAs during Drosophila early development and neuronal cell fate. The human homologue Staufen1 forms RNA-containing complexes that include proteins involved in translation and motor proteins to allow their movement within the cell, but the mechanism underlying translation repression in these complexes is poorly understood. Here we show that human Staufen1-containing complexes contain essential elements of the gene silencing apparatus, like Ago1-3 proteins, and we describe a set of miRNAs specifically associated to complexes containing human Staufen1. Among these, miR124 stands out as particularly relevant because it appears enriched in human Staufen1 complexes and is over-expressed upon differentiation of human neuroblastoma cells in vitro. In agreement with these findings, we show that expression of human Staufen1 is essential for proper dendritic arborisation during neuroblastoma cell differentiation, yet it is not necessary for maintenance of the differentiated state, and suggest potential human Staufen1 mRNA targets involved in this process.
Publication Title
Human Staufen1 associates to miRNAs involved in neuronal cell differentiation and is required for correct dendritic formation.
Sample Metadata Fields
Cell line
View Samples- Bos taurus
- 159 Downloadable Samples
- Affymetrix Bovine Genome Array (bovine)
Description
Infertility in lactating dairy cows is explained partially by the metabolic state associated with high milk production. The hypothesis was that lactating and non-lactating cows would differ in endometrial and placental transcriptomes during early pregnancy (day 28 to 42) and this difference would explain the predisposition for lactating cows to have embryonic loss at that time. Cows were either milked or not milked after calving. Reproductive [endometrium (caruncular and intercarunclar) and placenta] and liver tissues were collected on day 28, 35, and 42 of pregnancy. The primary hypothesis was rejected because no effect of lactation on mRNA abundance within reproductive tissues was found. Large differences within liver demonstrated the utility of the model to test an effect of lactation on tissue gene expression. Major changes in gene expression in reproductive tissues across time were found. Greater activation of the transcriptome for the recruitment and activation of macrophages was found in the endometrium and placenta. Changes in glucose metabolism between day 28 and 42 included greater mRNA abundance of rate-limiting genes for gluconeogenesis in intercaruncular endometrium and evidence for the establishment of aerobic glycolysis (Warburg effect) in the placenta. Temporal changes were predicted to be controlled by CSF1, PDGFB, and JUN. Production of nitric oxide and reactive oxygen species by macrophages was a mechanism to promote angiogenesis in the endometrium. Reported differences in pregnancy development for lactating versus non-lactating cows could be explained by systemic glucose availability to the conceptus and appear to be independent of the endometrial and placental transcriptomes.
Publication Title
The transcriptome of the endometrium and placenta is associated with pregnancy development but not lactation status in dairy cows.
Sample Metadata Fields
Specimen part
View Samples