Most metabolic studies are conducted in male animals; thus, the molecular mechanism controlling gender-specific pathways has been neglected, including sex-dependent responses to peroxisome proliferator-activated receptors (PPARs). Here we show that PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and inflammation. In males, this effect is reproduced by the administration of synthetic PPARalpha ligand. Using the steroid hydroxylase gene Cyp7b1 as a model, we elucidated the molecular mechanism of this PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggers the interaction of PPARalpha with the GA-binding protein alpha bound to the target promoter. Histone deacetylase is then recruited, and histones and adjacent Sp1-binding site are methylated. These events result in the loss of Sp1-stimulated expression, and thus the down-regulation of Cyp7b1. Physiologically, this repression confers protection against estrogen-induced intrahepatic cholestasis, paving the way for a novel therapy against the most common hepatic disease during pregnancy.
Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.
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View Samplesconsequences of astrocytes on GSCs, gene expression profiles generated from glioblastoma stem-like cells grown alone (mono-culture) and compared to those generated 48h after the initiation of co-culture with astrocytes
Coculture with astrocytes reduces the radiosensitivity of glioblastoma stem-like cells and identifies additional targets for radiosensitization.
Specimen part, Subject
View SamplesDefining radioresponse using the translatome and the transcriptome to identify functional consequences of radiation.
Polysome Profiling Links Translational Control to the Radioresponse of Glioblastoma Stem-like Cells.
Specimen part, Cell line, Treatment, Time
View SamplesInborn errors of lipid metabolism illustrate the importance of proper milk fat oxidation in newborn mammals. In the liver, a remarkable lipid catabolic competence is present at birth; however, it is unclear how this critical trait is acquired and regulated. In this work, we found that the genes required for milk lipid catabolism are already transcribed before birth in the term fetus (E19.5) and controlled by the peroxisome-proliferator activated receptor alpha (PPAR) in mouse liver. The developmental activity of PPAR strongly regulates fatty acid oxidation genes. Two days after birth (P2), during milk suckling, PPAR-null mice develop a congenital steatosis and milk protein oxidation is de-repressed to fuel an alternative energy pathway that maintains glucose homeostasis and postnatal growth. Our results demonstrate for the first time, the developmental role of PPAR in regulating the metabolic ability to use maternal milk as fuel in the early days of life.
Glucocorticoid receptor-PPARα axis in fetal mouse liver prepares neonates for milk lipid catabolism.
Specimen part
View SamplesInborn errors of lipid metabolism illustrate the importance of proper milk fat oxidation in newborn mammals. In the liver, a remarkable lipid catabolic competence is present at birth; however, it is unclear how this critical trait is acquired and regulated. In this work, we found that the genes required for milk lipid catabolism are already transcribed before birth in the term fetus (E19.5) and controlled by the peroxisome-proliferator activated receptor alpha (PPAR) in mouse liver. The developmental activity of PPAR strongly regulates fatty acid oxidation genes. Two days after birth (P2), during milk suckling, PPAR-null mice develop a congenital steatosis and milk protein oxidation is de-repressed to fuel an alternative energy pathway that maintains glucose homeostasis and postnatal growth. Our results demonstrate for the first time, the developmental role of PPAR in regulating the metabolic ability to use maternal milk as fuel in the early days of life.
Glucocorticoid receptor-PPARα axis in fetal mouse liver prepares neonates for milk lipid catabolism.
Sex, Specimen part
View SamplesAnalysis of white adipose tissue of PPARb/d knockout mice. Data may point towards putative target genes of PPARb/d and thus the function of PPARb/d in white adipose tissue. Datasets were used to identify glycogen synthase 2 as novel PPAR target.
Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors.
Sex, Age, Specimen part
View SamplesPeroxisome proliferator-activated receptor beta/delta protects against obesity by reducing dyslipidemia and insulin resistance via effects in various organs, including muscle, adipose tissue, liver, and heart. However, nothing is known about the function of PPAR-beta in pancreas, a prime organ in the control of glucose metabolism. To gain insight into so far hypothetical functions of this PPAR isotype in insulin production, we specifically ablated Ppar-beta in pancreas. The mutated mice developed a chronic hyperinsulinemia, due to an increase in both beta-cell mass and insulin secretion. Gene expression profiling indicated a broad repressive function of PPAR-beta impacting the vesicular compartment, actin cytoskeleton, and metabolism of glucose and fatty acids. Analyses of insulin release from the islets revealed an increased second-phase glucose-stimulated insulin secretion. Higher levels of PKD, PKC-delta and diacyglycerol in mutated animals lead to an enhanced formation of trans-Golgi network (TGN)-to-plasma-membrane transport carriers in concert with F-actin disassembly, which resulted in increased insulin secretion and its associated systemic effects. Taken together, these results provide evidence for PPAR-beta playing a repressive role on beta-cell growth and insulin exocytosis, which shed new light on its anti-obesity action.
PPARβ/δ affects pancreatic β cell mass and insulin secretion in mice.
Age, Specimen part
View SamplesAnalysis of alternative splicing in heart (left ventricles) samples of 3 adult DM1 patients versus 3 adult controls Overall design: PolyA RNA from left ventricles (heart) of 3 controls and 3 DM1 patients were analysed by massive parrallel sequencing
Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
No sample metadata fields
View SamplesAnalysis of alternative splicing of left ventricles heart samples of 3 DM1 adult versus 3 adult controls
Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
Specimen part, Disease, Disease stage
View SamplesUstilago maydis is a plant-pathogenic fungus that establishes a biotrophic relationship with its host Zea mays. The biotrophic interaction is initiated upon host penetration, and involves expansion of the host plasma membrane around hyphae, which is thought to facilitate the exchange of nutrients and virulence factors. Transcriptional regulators involved in the establishment of an infectious dikaryon and penetration into the host have been identified, however, regulators involved in the post-penetration stages remained to be elucidated. In the study we report the identification of an Ustilago maydis forkhead transcription factor, Fox1, which is exclusively expressed during biotrophic development. Deletion of fox1 results in reduced virulence and impaired tumour development in planta. fox1 hyphae induce plant defences including the overproduction and accumulation of H2O2 in and around infected cells. This oxidative burst acts as an intercellular signal, which elicits a specific host defence response phenotypically represented by the encasement of proliferating hyphae in extensions of the plant cell wall. Maize microarrays experiments were performed to identify genes involved in the observed plant defence responses on leaf tissue infected with U. maydis strain SG200fox1 4 dpi.
The Ustilago maydis forkhead transcription factor Fox1 is involved in the regulation of genes required for the attenuation of plant defenses during pathogenic development.
Specimen part
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