Mus musculus
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ABSTRACT:
PROVIDER: PRJNA227203 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: The goal of this study was to determine biological consequences during liver regeneration following partial hepatectomy in mice by next-generation sequencing. A particular interest was to compare mice with either a floxed b-PDGFR allele to mice that harbored a deletion of b-PDGFR in hepatic stellate cells (HSCs), by crossing b-PDGFR fl/fl mice with transgenic GFAP-Cre mice. Methods: b-PDGFR fl/fl mice or mice with a HSC-specific deletion of b-PDGFR underwent either sham operation or 70% partial hepatectomy. Following 72 hours, livers were collected and total RNA was extracted using tizol, followed by a purification using Quiagen spin columns including an on-column DNAse digestion step. Conclusion: Our study represents a detailed analysis of hepatic transcriptome, with biologic replicates, generated by RNA-seq technology of livers following sham operation or partial hepatectomy in b-PDGFR fl/fl mice or b-PDGFRfl/fl/GRAP-Cre mice. Whole liver mRNA profiles of sham operated livers or livers collected 72hours after partial hepatectomy of beta-PDGFR fl/fl and beta-PDGFR fl/fl/GFAP-Cre (creating a hepatic stellate cell-specific deletion of b-PDGFR) mice were generated by deep sequencing, in duplicate, using Illumina HiSeq2000.
2013-11-08 | E-GEOD-52234 | biostudies-arrayexpress
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone.
2015-02-19 | GSE52253 | GEO
Project description:Purpose: The goal of this study was to determine biological consequences during liver regeneration following partial hepatectomy in mice by next-generation sequencing. A particular interest was to compare mice with either a floxed b-PDGFR allele to mice that harbored a deletion of b-PDGFR in hepatic stellate cells (HSCs), by crossing b-PDGFR fl/fl mice with transgenic GFAP-Cre mice. Methods: b-PDGFR fl/fl mice or mice with a HSC-specific deletion of b-PDGFR underwent either sham operation or 70% partial hepatectomy. Following 72 hours, livers were collected and total RNA was extracted using tizol, followed by a purification using Quiagen spin columns including an on-column DNAse digestion step. Conclusion: Our study represents a detailed analysis of hepatic transcriptome, with biologic replicates, generated by RNA-seq technology of livers following sham operation or partial hepatectomy in b-PDGFR fl/fl mice or b-PDGFRfl/fl/GRAP-Cre mice.
2013-11-08 | GSE52234 | GEO
Project description:The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As the platelet derived growth factor receptor (PDGFR) pathway is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway in HSC. To study the role of synectin in the development of liver fibrosis, mice with selective deletion of synectin from HSC were generated and found to be protected from fibrosis. RNAseq revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes including PDGFR-β, but not PDGFR-α. Chromatin Immunoprecipitation assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300. In contradistinction, synectin was found to regulate PDGFR-α through an alternative mechanism: protection from autophagic degradation. Site directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues is responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF dependent proliferation and migration after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin expression. This work provides insight into differential transcriptional and post-translational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.
2017-12-31 | GSE93629 | GEO
Project description:We used microarrays to detail the gene expression profile during WAT -beige transition by treatment of beta adrenergic receptor agonist .
2014-03-15 | GSE55934 | GEO
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.
| S-EPMC8784167 | biostudies-literature
Project description:Deactivation of Hepatic Stellate Cells during Liver Fibrosis Resolution in Mice
| PRJNA168305 | ENA
Project description:Sex differences in liver gene expression are dictated by sex-differences in circulating growth hormone (GH) profiles. Presently, the pituitary hormone dependence of mouse liver gene expression was investigated on a global scale to discover sex-specific early GH response genes that might contribute to sex-specific regulation of downstream GH targets and to ascertain whether intrinsic sex-differences characterize hepatic responses to plasma GH stimulation. RNA expression analysis using 41,000-feature microarrays revealed two distinct classes of sex-specific mouse liver genes: genes subject to positive regulation (class-I) and genes subject to negative regulation by pituitary hormones (class-II). Genes activated or repressed in hypophysectomized (Hypox) mouse liver within 30-90min of GH pulse treatment at a physiological dose were identified as direct targets of GH action (early response genes). Intrinsic sex-differences in the GH responsiveness of a subset of these early response genes were observed. Notably, 45 male-specific genes, including five encoding transcriptional regulators that may mediate downstream sex-specific transcriptional responses, were rapidly induced by GH (within 30min) in Hypox male but not Hypox female mouse liver. The early GH response genes were enriched in 29 male-specific targets of the transcription factor Mef2, whose activation in hepatic stellate cells is associated with liver fibrosis leading to hepatocellular carcinoma, a male-predominant disease. Thus, the rapid activation by GH pulses of certain sex-specific genes is modulated by intrinsic sex-specific factors, which may be associated with prior hormone exposure (epigenetic mechanisms) or genetic factors that are pituitary-independent, and could contribute to sex-differences in predisposition to liver cancer or other hepatic pathophysiologies.
2010-01-27 | GSE17644 | GEO