The genomic landscape of hepatic tissue affected by nonalcoholic steatohepatitis (NASH) in severely obese adolescents undergoing bariatric surgery is unknown. Our purpose here was to uncover genomic profiles of obese controls, and obese cases with nonalcoholic fatty liver disease (NAFLD), borderline nonalcoholic steatohepatitis, and definite nonalcoholic steatohepatitis, in order to clarify molecular functions, biological processes, and pathways that are dysregulated in nonalcoholic steatohepatitis in the severely obese adolescent.
High Prevalence of Nonalcoholic Fatty Liver Disease in Adolescents Undergoing Bariatric Surgery.
Sex, Disease
View SamplesWe developed a 5''RNA-seq methodology to concurrently assess gene expression and start-site usage changes. We applied this methodology to study hypertrophic cardiomyopathy in mice harboring a human deleterious mutation. Overall design: 5''RNA-seq analysis of transcriptomes from mouse hearts with or without hypertrophic cardiomyopathy. Biological replicates were pooled into a single sequencing run. 5''RNA-seq methodology consists of enhanced sequencing of 5'' ends and computational assessment of changes at start-sites of genes.
5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy.
No sample metadata fields
View SamplesData on the temporal dynamics of human placental gene expression is scarce. We have completed the first whole-genome profiling of human placental gene expression dynamics (GeneChips, Affymetrix) from early to mid- gestation (10 samples; gestational weeks 5 to 18) and report 154 genes with considerable change in transcript levels (FDR P<0.1). Functional enrichment analysis revealed >200 GO categories that are statistically over-represented among 105 genes with dynamically increasing transcript levels. Analysis in an extended sample (n=43; gestational weeks 5 to 41) conformed a highly significant (FDR P<0.05) expressional peak in mid-gestation placenta for ten genes: BMP5, CCNG2, CDH11, FST, GATM, GPR183, ITGBL1, PLAGL1, SLC16A10, STC1. A central hypothesis of our study states that the aberrant expression of genes characteristic to mid-gestation placenta may contribute to affected fetal growth, maternal preeclampsia (PE) or gestational diabetes (GD). The gene STC1 coding for Stanniocalcin 1 (STC1) was identified with a sharp placental expressional peak in mid-gestation, increased mRNA levels at term and significantly elevated STC1 protein levels in post-partum maternal plasma in all pregnancy complications. The highest STC1 levels were identified in women, who developed simultaneously PE and delivered an SGA baby (median 731 vs 418 pg/ml in controls; P=0.001). CCNG2 and LYPD6 exhibited significantly increased placental mRNA expression and enhanced intensity of immunohistochemistry staining in placental sections all studied in GD and PE cases. Aberrant expression of mid-gestation specific genes in pregnancy complications at term indicates the importance of the fine-scale tuning of the temporal dynamics of transcription regulation in placenta. Observed significantly elevated plasma STC1 in complicated pregnancies warrants further investigations of its potential as a biomarker. Interestingly, a majority of genes with high expression in mid-gestation placenta have also been implicated in adult complex disease. This observation promotes a recently opened discussion on the role of placenta in developmental programming.
Mid-gestational gene expression profile in placenta and link to pregnancy complications.
Specimen part
View SamplesCbtOE (Tim-gal4; UAS-cbtFLAG), Tim-gal4 (control for CbtOE), cbtRNAi (Tim-gal4-UAS-Dcr2-UAS-cbtIR-cbtE1) and Tim-gal4;UAS-Dcr2 (control for CbtRNAi) flies. Flies were entrained in LD (light: dark) condition for 3-4 days and harvested at six time points: ZT3, ZT7, ZT11, ZT15, ZT19, ZT23 Fly heads were collected, RNA was extracted and RNA-seq libraries were prepared as previously described (Engreitz et al., 2013) Overall design: Three samples of cbtRNAi and three samples of their controls. Two samples of cbtOE with two samples of their controls.
The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing.
Specimen part, Subject, Time
View SamplesMaintaining metabolic homeostasis in response to fluctuating nutrient intake requires intricate coordination between tissues of multicellular animals. The insulin/glucagon axis is well known to hormonally coordinate organism-wide carbohydrate metabolism. The ChREBP/Mondo-Mlx transcription factors regulate glycolytic and lipogenic genes locally in hepatocytes and adipocytes, but its role in systemic metabolic homeostasis has remained poorly understood. We demonstrate that Mondo-Mlx controls gene activity in several peripheral tissues of Drosophila melanogaster, where it regulates nutrient digestion and transport as well as carbohydrate, amino acid and lipid metabolism. In addition to directly regulating metabolic genes Mondo-Mlx controls a regulatory network composed of the Activin ligand Dawdle and GLI similar transcription factor Sugarbabe. Dawdle and Sugarbabe contribute to the regulation of a subset of Mondo-Mlx-dependent processes, including sugar-induced de novo synthesis of serine and fatty acids. In summary, our study establishes Mondo-Mlx sugar sensor as a master regulator of organismal metabolic homeostasis upon sugar feeding. Overall design: Control (sug17d/+) and sugarbabe null mutant (sug17d/sug def) third instar larvae were fed control low sugar or high sugar diet and total RNA was extracted from the whole larvae.
Mondo-Mlx Mediates Organismal Sugar Sensing through the Gli-Similar Transcription Factor Sugarbabe.
Specimen part, Subject
View SamplesControl (+/cbtE1-UAS-cbt RNAi) or cabut RNAi flies (Tim-gal4, UAS-cbt RNAi) were starved for 16 hours and then exposed to food containing different concentrations of sucrose: 0, 25, 50 and 100 % for 18 hours. Fly heads were collected, RNA was extracted and RNA-seq libraries were prepared as previously described (Engreitz et al., 2013) Overall design: For each sucrose concentration, two samples of cabut RNAi flies and one sample of control flies were sequenced.
The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing.
Specimen part, Subject
View SamplesMicroarray data obtained from control, cbtRNAi (cabut RNAi), and cbtOE (cabut overexpression) flies. From each strain, fly heads at two different time points during the daynight cycle (ZT3 and ZT153) were collected.
The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing.
Specimen part, Treatment
View SamplesIntestinal calcium absorption is the sole pathway to supply calcium to the body and duodenum is the most efficient site of calcium absorption. Endurance exercise with moderate intensity significantly increased the intestinal calcium absorption. The unloaded non-impact excercise, such as swimming may enhance calcium absorption. However, the cellular and molecular mechanisms of this change have not been investigated. Thus, a genome-wide study by using microarray should reveal changes in the expression of several transporter genes in the intestinal absorptive cells of swimming excercised rats.
Endurance swimming stimulates transepithelial calcium transport and alters the expression of genes related to calcium absorption in the intestine of rats.
Sex, Age
View SamplesIn addition to their role in the development and function of the reproductive system, estrogens have significant anti-inflammatory properties. Although both estrogen receptors (ERs) can mediate anti-inflammatory actions, ERbeta is a more desirable therapeutic target because ERalpha mediates the proliferative effects of estrogens on the mammary gland and uterus. In fact, selective ERbeta agonists have beneficial effects in preclinical models involving inflammation without causing growth-promoting effects on the uterus or mammary gland. However, their mechanism of action is unclear. The purpose of this study was to use microarray analysis to determine whether ERbeta-selective compounds produce their anti-inflammatory effects by repressing transcription of proinflammatory genes. We identified 49 genes that were activated by TNF-alpha in human osteosarcoma U2OS cells expressing ERbeta. Estradiol treatment significantly reduced the activation by TNF-alpha on 18 genes via ERbeta or ERalpha. Most repressed genes were inflammatory genes, such as TNF-alpha, IL-6, and CSF2. Three ERbeta-selective compounds, ERB-041, WAY-202196, and WAY-214156, repressed the expression of these and other inflammatory genes. ERB-041 was the most ERbeta-selective compound, whereas WAY-202196 and WAY-214156 were the most potent. The ERbeta-selective compounds repressed inflammatory genes by recruiting the coactivator, SRC-2. ERB-041 also repressed cytokine genes in PBMCs, demonstrating that ERbeta-selective estrogens have anti-inflammatory properties in immune cells. Our study suggests that the anti-inflammatory effects of ERB-041 and other ERbeta-selective estrogens in animal models are due to transcriptional repression of proinflammatory genes. These compounds might represent a new class of drugs to treat inflammatory disorders.
Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes.
No sample metadata fields
View SamplesMetazoan development depends on accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation is brought about by global changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell fate determination is less well understood. Using a human embryonic stem cell model, we identified the vertebrate-specific ubiquitin ligase Cul3KBTBD8 as an essential regulator of neural crest cell formation. Cul3KBTBD8 monoubiquitylates NOLC1 and its paralog TCOF1, whose mutation underlies the developmental disease Treacher Collins Syndrome that is characterized by a loss of cranial neural crest cells. Ubiquitylation of NOLC1 and TCOF1 drives formation of a platform that connects RNA polymerase I with ribosome modification enzymes, thereby altering the translational program of differentiating cells to support the generation of neural crest cells. We conclude that the dynamic regulation of ribosome function is an important feature of cell fate determination.
Cell-fate determination by ubiquitin-dependent regulation of translation.
Cell line
View Samples