OBJECTIVE: To characterize the hormonal milieu and adipose gene expression in response to catch-up growth (CUG), a growth pattern associated with obesity and diabetes risk, in a mouse model of low birth weight (LBW). RESEARCH DESIGN AND METHODS: ICR mice were food restricted by 50% from gestational days 12.5-18.5, reducing offspring birth weight by 25%. During the suckling period, dams were either fed ad libitum, permitting CUG in offspring, or food restricted, preventing CUG. Offspring were killed at age 3 weeks, and gonadal fat was removed for RNA extraction, array analysis, RT-PCR, and evaluation of cell size and number. Serum insulin, thyroxine (T4), corticosterone, and adipokines were measured.
Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice.
Sex, Age, Specimen part
View SamplesThe goal is to examine the transcriptome of ESCs with different Myc levels Overall design: In order to analyse the transcriptome, mESC population was sorted in 3 groups depending on Myc levels
Pluripotency Surveillance by Myc-Driven Competitive Elimination of Differentiating Cells.
Specimen part, Cell line, Subject
View SamplesThe goal of this study is to analyse the transcriptome of WT and Myc-overexpressing ESCs in iMOS T1-Myc mosaic cultures. Overall design: Homozygous iMOS T1-Myc ESC cultures (Claveria et al., 2013) were treated with 20µM 4-hydroxytamoxifen for 24 hours to generate a mosaic of cell populations containing two, one or no extra Myc and EYFP copies. 24 hours after tamoxifen removal, cells were sorted according to their EYFP expression levels and populations with two extra Myc and EYFP copies and with no extra Myc and EYFP copies were collected. Uninduced homozygous iMOS T1-Myc ESC cultures were also sorted and collected as a control. Three biological replicas were included for each condition.
Pluripotency Surveillance by Myc-Driven Competitive Elimination of Differentiating Cells.
Subject
View SamplesInsulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) and is even present in offspring of diabetic parents. However, molecular mediators of insulin resistance remain unclear. We find that the top-ranking gene set in expression analysis of muscle from humans with T2D and normoglycemic insulin resistant subjects with parental family history (FH+) of T2D is increased expression of actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator MKL1. Furthermore, the SRF activator STARS is upregulated in FH+ and T2D and inversely correlated with insulin sensitivity. These patterns are recapitulated in insulin resistant mice, and linked to alterations in two other regulators of this pathway: reduced G-actin and increased nuclear localization of MKL1. Both genetic and pharmacologic manipulation of STARS/MKL1/SRF pathway significantly alter insulin action: 1) Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation; 2) reduced STARS expression increased insulin signalling and glucose uptake, and 3) SRF inhibition by CCG-1423 reduced nuclear MKL1, improved glucose uptake, and improved glucose tolerance in insulin resistant mice in vivo. Thus, SRF pathway alterations are a signature of insulin resistance which may also contribute to T2D pathogenesis and be a novel therapeutic target.
Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance.
Sex, Age, Specimen part
View SamplesBackground
Gene expression profile of cervical and skin tissues from human papillomavirus type 16 E6 transgenic mice.
No sample metadata fields
View SamplesThe epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CBP, a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioral adaptations to environmental enrichment (EE). Morphological and behavioral analyses demonstrated that EE ameliorates deficits associated to CBP-deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-enhanced spatial navigation and patter separation ability. These defects correlated with an attenuation of the transcriptional program induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics.
CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement.
Sex, Age, Specimen part
View SamplesThe objective of this study was to elucidate age-related differences in gene expression profiles of rhesus monkey bone marrow-derived mesenchymal stem cells (rhMSC) obtained from fetal, infant, and adult donors relevant to their growth and other properties. Although a high degree of similarity was observed in the rhMSC gene expression profiles when comparing the three age groups, significant differences were found that strongly parallel gene expression profiles of human MSC. The potential functional relevance of differential gene expression was most apparent when comparing fetal and adult rhMSC transcript profiles. Overall, the observed gene expression profiles are consistent with a loss of rhMSC pluripotency and proliferative capacity with advancing donor age. In addition, these data highlight the importance of use of non-human primates as a model system for studying the properties of human stem cells.
Age-related gene expression profiles of rhesus monkey bone marrow-derived mesenchymal stem cells.
No sample metadata fields
View SamplesThe rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11c?Vhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhlfl/fl, AMs from CD11c?Vhl mice do not revert pulmonary alveolar proteinosis when transplanted into Csf2rb-/- mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their oxygen sensing capacity. Overall design: BAL AMs were pooled from 5-7 age and sex-matched mice per genotype and further purified by positive selection with anti-CD11c-microbeads (Miltenyi Biotec), following manufacturer's instructions. Cell lysis was performed with buffer RLT (Qiagen), containing 10µ/ml ß-mercaptoethanol and RNA was isolated with RNeasy Plus Mini Kit (Qiagen). RNA concentration and integrity were determined with an Agilent 2100 Bioanalyzer (Caliper Life Science). Samples with RNA integrity values > 8 were further processed. A total of 3 pools per genotype were used for RNA Seq.
Von Hippel-Lindau Protein Is Required for Optimal Alveolar Macrophage Terminal Differentiation, Self-Renewal, and Function.
Treatment, Subject
View SamplesAlternative mRNA splicing provides transcript diversity and has been proposed to contribute to several human diseases. Here, we demonstrate that expression of genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. To determine the metabolic impact of reduced splicing factor expression, we further evaluated the splicing factor, SFRS10, identified as down-regulated in obese human liver and skeletal muscle and in high fat fed rodents. siRNA-mediated reductions in SFRS10 expression induced lipogenesis and lipid accumulation in cultured hepatocytes. Moreover, SFRS10 heterozygous mice have both increased hepatic lipogenic gene expression and hypertriglyceridemia. We also demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10, with reduced SFRS10 levels favoring the lipogenic isoform of LPIN1. Importantly, LPIN1-specific siRNA abolished the lipogenic effects of decreased SFRS10 expression. Together, our results indicate reduced expression of SFRS10 alters LPIN1 splicing and induces lipogenesis, demonstrating that reduced splicing factor expression observed in human tissues may contribute to metabolic phenotypes associated with human obesity.
Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis.
Age, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Rapamycin response in tumorigenic and non-tumorigenic hepatic cell lines.
No sample metadata fields
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