This SuperSeries is composed of the SubSeries listed below.
Reconstruction of gene regulatory networks reveals chromatin remodelers and key transcription factors in tumorigenesis.
Specimen part, Cell line
View SamplesThe seed coat of black (iRT) soybean with the dominant R allele begins to accumulate cyanic pigments at the transition stage of seed development (300 400 mg fresh seed weight), whereas the brown (irT) nearly-isogenic seed coat with the recessive r allele lacks cyanic pigments at all stages of seed development.
Combined analysis of transcriptome and metabolite data reveals extensive differences between black and brown nearly-isogenic soybean (Glycine max) seed coats enabling the identification of pigment isogenes.
Specimen part
View SamplesThe mechanistic links between transcription factors and the epigenetic landscape, which coordinate the deregulation of gene networks during cell transformation are largely unknown. We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. By combining transcriptome and epigenome data for each step during transformation and by integrating transcription factor (TF) - target gene associations, we identified 142 Tfs and 24 chromatin remodelers/modifiers (CRMs), which are preferentially associated with specific co-expression paths that originate from deregulated gene programming during tumorigenesis. These Tfs are involved in the regulation of divers processes, including cell differentiation, immune response and establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes, which are not only co-regulated but also functionally related. Further decortication of TF targets enabled us to define potential key regulators of cell transformation, which are engaged in RNA metabolism and chromatin remodelling. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of gene regulatory networks that are altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system.
Reconstruction of gene regulatory networks reveals chromatin remodelers and key transcription factors in tumorigenesis.
Specimen part, Cell line
View SamplesDevelopment is a complex and well-defined process characterized by rapid cell proliferation and apoptosis. At this stage in life, a developmentally young organism is more sensitive to toxicants and other stressors when compared to an adult. In response to pro-oxidant exposure, members of the Cap’n’Collar (CNC) basic leucine zipper (b-ZIP) transcription factor family (including the Nfe2-related factors, Nrfs) activate the expression of genes that contribute to reduced toxicity. Here, we studied the role of the Nrf protein, Nfe2, in the developmental response to pro-oxidant exposure in the zebrafish. Following acute waterborne exposures to diquat or tert-buytlhydroperoxide (tBOOH) at three developmental stages, wildtype (WT) and nfe2 knockout (KO) embryos and larvae were morphologically scored and their transcriptomes sequenced. Overall design: Wildtype animals were on the AB background and an additional germline nfe2 knockout strain were created by disruption of the nfe2 reading frame. Waterborne exposures to either diquat or tBOOH were carried out at three different developmental stages: 2 hours post fertilization (hpf), 48hpf, and 96hpf in 3 pools of 30 embryos per condition. Animals were exposed to no treatment, 20µM diquat or 1mM tBOOH for a 4-hour dosing period. Total RNA was isolated from pooled animals and 50 bp, paired end, libraries were sequenced using the Illumina HiSeq 2000 platform, with approximately 25 million reads per sample. Reads were then aligned to the Ensembl GRCz10 zebrafish reference genome using Tophat2 and raw counts data normalized using DESeq2. Gene annotation was from Ensemble for GRCz10.
The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Reconstructed cell fate-regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis.
Specimen part, Time
View SamplesWe have integrated dynamic RXRa binding, chromatin accessibility and promoter epigenetic status with the transcriptional activity inferred from RNA polymerase II mapping and transcription profiling. This demonstrated a temporal organization structure, in which early events are preferentially enriched for common GRNs, while cell fate specification is reflected by the activation of late programs in a cell-type specific manner. Furthermore, significant differences in cell lines' promoter status of genes associated with cell-line specific programs were inferred. Finally, a variety of transcription factors (TFs) playing a direct role in the signal transduction cascade downstream of the RXR/RAR initiated wiring were identified, several of them commonly regulated in both model systems, but in addition cell-type specific TF drivers were also identified.
Reconstructed cell fate-regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis.
Specimen part, Time
View SamplesWe studied adipose tissue from wild type mice, kinin B1 receptor knockout mice (B1KO), and B1KO mice with rescued expression of kinin B1 receptor selectively in fat.
Kinin B1 and B2 receptor deficiency protects against obesity induced by a high-fat diet and improves glucose tolerance in mice.
Sex, Age, Specimen part
View SamplesDifferent osteoprogenitors (SSC, BCSP, Thy+) were sorted after 2 days of JUN induction, followed by RNA extraction and microarray analysis
Expansion of Bone Precursors through Jun as a Novel Treatment for Osteoporosis-Associated Fractures.
Specimen part
View SamplesWe assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity.
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms.
Sex
View SamplesThe genetics of messenger RNA expression has been extensively studied in humans and other organisms, but little is known about genetic factors contributing to microRNA (miRNA) expression. We examined natural variation of miRNA expression in adipose tissue in a population of 200 men who have been carefully characterized for metabolic syndrome phenotypes as part of the METSIM study. We genotyped the subjects using high-density SNP microarrays and quantified the mRNA abundance using genome-wide expression arrays and miRNA abundance using next generation sequencing. We reliably quantified 356 miRNA species that were expressed in human adipose tissue, a limited number of which made up most of the expressed miRNAs. We mapped the miRNA abundance as an expression quantitative trait and determined cis regulation of expression for 9 of the miRNAs and of the processing of one miRNA (miR-28). The degree of genetic variation of miRNA expression was substantially less than that of mRNAs. For the majority of the miRNAs, genetic regulation of expression was independent of the host mRNA transcript expression. We also showed that for 108 miRNAs, mapped reads displayed widespread variation from the canonical sequence. We found a total of 24 miRNAs to be significantly associated with metabolic syndrome traits. We suggest a regulatory role for miR-204-5p which was predicted to inhibit ACACB, a key fatty acid oxidation enzyme that has been shown to play a role in regulating body fat and insulin resistance in adipose tissue. Overall design: miRNA expression profiling of adipose tissue isolated from 200 humans
Genetic regulation of human adipose microRNA expression and its consequences for metabolic traits.
Age, Specimen part, Subject
View Samples