Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Profiling liver from 5LO KO and WT B6 mice

ABSTRACT: To understand the effects of knocking out the 5-LO gene on gene expression in key metabolic target tissues liver. The 5LO KO mouse liver profiling data was analyzed by identifying genes that were up- and down-regulated at selected p value and fold change in the liver of 5LO KO mice compared to the corresponding WT B6 controls.

ORGANISM(S): Mus musculus

SUBMITTER: I-Ming Wang

PROVIDER: E-GEOD-38081 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers.

Wang I-Ming IM Zhang Bin B Yang Xia X Zhu Jun J Stepaniants Serguei S Zhang Chunsheng C Meng Qingying Q Peters Mette M He Yudong Y Ni Chester C Slipetz Deborah D Crackower Michael A MA Houshyar Hani H Tan Christopher M CM Asante-Appiah Ernest E O'Neill Gary G Luo Mingjuan Jane MJ Thieringer Rolf R Yuan Jeffrey J Chiu Chi-Sung CS Lum Pek Yee PY Lamb John J Boie Yves Y Wilkinson Hilary A HA Schadt Eric E EE Dai Hongyue H Roberts Christopher C

Molecular systems biology 20120717

Common inflammatome gene signatures as well as disease-specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co-expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue-specific Bayesian networks (BNs) built from multiple ...[more]

PMID: 22806142

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Project description:Background: Genetic elimination of c-Met signaling in the liver has been shown to impact many cellular pathways involved in repair, regeneration, lipid homeostasis and redox balance. In this study, we analyzed a nutritional model of hepatic steatosis in Met fl/fl ; Alb-Cre +/- (MetKO) mice in a 129SV/C57BL/6 background fed a high cholesterol diet for 30 days. Methods: Liver injury was determined by histopathology and plasma enzymes, transcriptomic changes were examined using gene expression microarrays, and evaluation of key molecules involved in liver damage and lipid homestasis were evaluated by Western blot analysis. Results: We observed that in comparison with wild type mice subjected to the same diet, MetKO mice developed a strong liver lipid deposition, inflammatory infiltration and increment in total bile acids synthesis and liver damage markers. Global transcriptomic changes analysis confirmed the steatosis and cholestasis induced by the high cholesterol diet. In addition, we found affected pathways related to amino acids, glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction. Oxidative stress exacerbation was corroborated by lipid and protein oxidation in liver tissue. To address further, Western blot studies revealed downregulation on Erk, NF-kB and Nrf2 survival pathways and target genes (cyclin D1, SOD1, gamma-GCS), an increment in proapoptotic proteins (p53, caspase 3) and changes in nuclear receptors such as RAR and RXR, which were increased, and CAR, FXR and PPAR alfa, which were decreased, in the MetKO diet. These results are in agreement with the steatosis and cholestasis phenotype. Conclusion: Our data provide evidence of c-Met signaling involvement in lipid metabolism, and bile acids synthesis and excretion. Disruption of these pathways leads to liver dysfunction, improper metabolism and hepatocellular damage. Global transcriptome changes between WT mice vs. c-Met KO mice fed a 2% cholesterol and 0.5% sodium cholate diet (high cholesterol) or a Chow regular diet (Chow) as control. Mice were fed a high cholesterol or chow regular diet for 30 days. Liver tissue was obtained, and RNA was extracted and subjected to Illumina microarray analysis.

Project description:Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2/Abcb4-knockout (Mdr2-KO) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation (MeDIP) followed by hybridization with Agilent CpG Islands (CGIs) microarrays we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-KO liver compared to age-matched controls. Methylation of thirty among these genes was highly specific to the studied HCC model. We revealed that in most tested cases, the observed hypermethylation resulted from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2-KO liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. This decrease could result from a less efficient age-dependent demethylation of specific CpG sites in the liver of Mdr2-KO mutants, as described above. Expression of some tested hypermethylated genes was increased in Mdr2-KO livers compared to controls (28%), others were either similarly expressed (44%), or not expressed in the liver (28%). Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-KO compared to control livers affected either hepatocyte, or non-hepatocyte, or both fractions. There was only episodic correlation between changes of gene methylation and expression in cell fractions. Conclusion: Chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as markers of an increased regenerative activity and of a precancerous microenvironment in the chronically inflamed liver. Two-condition experiment, Mdr2-KO vs Mdr2-/+ liver tissue from 12m-old male FVB strain mice. Biological replicates: 3 control replicates, 3 knockout replicates.

Dataset Information

Profiling liver from 5LO KO and WT B6 mice

Publications

Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers.

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