Expression data from GNMT and MAT1A knockout models that develop all the stages of non-alcoholic fatty liver disease including hepatocellular carcinoma [MAT1A_15months]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE63062 | GEO | 2014/11/07
SECONDARY ACCESSION(S): PRJNA266544
REPOSITORIES: GEO
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Project description:Liver global gene expression patterns of 9 GNMT-knockout mice histopathologically determined to have non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) together with 10 MAT1A-knockout mice histopathologically determined to have steatosis and NASH. All these have their respective wild type patterns. These were analyzed to define signatures to study the pathogenesis of NAFLD-derived HCC, explore which subtypes of cancers can be investigated using mouse models and define a signature of HCC differential survival that can be used to characterize HCC subtypes of different survival derived from mixed etiologies.
2014-11-07 | GSE63027 | GEO
Project description:Methionine adenosyltransferase (MAT) enzymes generate SAMe (S-adenosylmethionine), the main biological methyl donor. There are two MAT encoding genes in mammals (Mat1a and Mat2a), which show different activities and cellular distribution. Mat1a encodes the enzyme mainly expressed in normal liver. Mat1a ablation in mice results in the spontaneous development of non-alcoholic steatohepatitis (NASH). We observed that SAMe depletion in Mat1a KO mice had three main effects on hepatic lipid metabolism: 1) impaired TG (triglyceride) export via VLDL; 2) impaired mitochondrial FA (fatty acid) oxidation (as evidenced by membrane depolarization, downregulation of Phb1 (prohibitin 1, a mitochondrial chaperone protein) and Mcj/Dnajc15 (endogenous mitochondrial repressor of respiratory chain), and accumulation of long-chain acylcarnitines); and 3) increased FA uptake. The convergence of these three factors induced TG accumulation in LD (lipid droplets). LD expansion confronts hepatocytes with a high demand of PC (phosphatidylcholine) molecules to cover the LD surface since other phospholipids, such as PE (phosphatidylethanolamine), cannot stabilize LD and prevent coalescence. In Mat1a KO this situation is aggravated, since SAMe-dependent PC synthesis via PE methylation is decreased, the PC/PE ratio reduced and mitochondrial FA oxidation impaired. To put a brake to this drain of PC molecules to LD, FA are rerouted in Mat1a KO mice liver to other catabolic (endoplasmic reticulum and peroxisome oxidation) and biosynthetic (ceramides synthesis) pathways, causing oxidative stress, inflammation and fibrosis. SAMe treatment for two months in 8-9 month old Mat1a KO mice ameliorated mitochondrial dysfunction (reduces membrane depolarization, improves Phb1 and Mcj expression, and increases SAMe transport to mitochondria) improving FA oxidation efficiency (FA and acylcarnitine levels decrease), which results in a drastic reduction in TG accumulation. SAMe treatment in Mat1a KO mice resulted in more PC available for proper membrane function, improving liver lipid homeostasis, histology (H&E, Sudan red, Sirius red) and liver injury (ALT, AST).
2017-02-02 | GSE77082 | GEO
Project description:Methionine adenosyltransferase (MAT) enzymes generate SAMe (S-adenosylmethionine), the main biological methyl donor. There are two MAT encoding genes in mammals (Mat1a and Mat2a), which show different activities and cellular distribution. Mat1a encodes the enzyme mainly expressed in normal liver. Mat1a ablation in mice results in the spontaneous development of non-alcoholic steatohepatitis (NASH). We observed that SAMe depletion in Mat1a KO mice had three main effects on hepatic lipid metabolism: 1) impaired TG (triglyceride) export via VLDL; 2) impaired mitochondrial FA (fatty acid) oxidation (as evidenced by membrane depolarization, downregulation of Phb1 (prohibitin 1, a mitochondrial chaperone protein) and Mcj/Dnajc15 (endogenous mitochondrial repressor of respiratory chain), and accumulation of long-chain acylcarnitines); and 3) increased FA uptake. The convergence of these three factors induced TG accumulation in LD (lipid droplets). LD expansion confronts hepatocytes with a high demand of PC (phosphatidylcholine) molecules to cover the LD surface since other phospholipids, such as PE (phosphatidylethanolamine), cannot stabilize LD and prevent coalescence. In Mat1a KO this situation is aggravated, since SAMe-dependent PC synthesis via PE methylation is decreased, the PC/PE ratio reduced and mitochondrial FA oxidation impaired. To put a brake to this drain of PC molecules to LD, FA are rerouted in Mat1a KO mice liver to other catabolic (endoplasmic reticulum and peroxisome oxidation) and biosynthetic (ceramides synthesis) pathways, causing oxidative stress, inflammation and fibrosis. SAMe treatment for two months in 8-9 month old Mat1a KO mice ameliorated mitochondrial dysfunction (reduces membrane depolarization, improves Phb1 and Mcj expression, and increases SAMe transport to mitochondria) improving FA oxidation efficiency (FA and acylcarnitine levels decrease), which results in a drastic reduction in TG accumulation. SAMe treatment in Mat1a KO mice resulted in more PC available for proper membrane function, improving liver lipid homeostasis, histology (H&E, Sudan red, Sirius red) and liver injury (ALT, AST).
2017-02-02 | GSE77079 | GEO
Project description:The "methionine cycle" plays a critical role in the regulation of concentrations of (S)-adenosylmethionine (AdoMet), the major biological methyl donor. We set out to study sequence variation in genes encoding the enzyme that synthesizes AdoMet in liver, methionine adenosyltransferase 1A (MAT1A) and the major hepatic AdoMet using enzyme, glycine N-methyltransferase (GNMT), as well as functional implications of that variation. We resequenced MAT1A and GNMT using DNA from 288 subjects of three ethnicities, followed by functional genomic and genotype-phenotype correlation studies performed with 268 hepatic biopsy samples. We identified 44 and 42 polymorphisms in MAT1A and GNMT, respectively. Quantitative Western blot analyses for the human liver samples showed large individual variation in MAT1A and GNMT protein expression. Genotype-phenotype correlation identified two genotyped single-nucleotide polymorphisms (SNPs), reference SNP (rs) 9471976 (corrected p = 3.9 × 10(-10)) and rs11752813 (corrected p = 1.8 × 10(-5)), and 42 imputed SNPs surrounding GNMT that were significantly associated with hepatic GNMT protein levels (corrected p values < 0.01). Reporter gene studies showed that variant alleles for both genotyped SNPs resulted in decreased transcriptional activity. Correlation analyses among hepatic protein levels for methionine cycle enzymes showed significant correlations between GNMT and MAT1A (p = 1.5 × 10(-3)) and between GNMT and betaine homocysteine methyltransferase (p = 1.6 × 10(-7)). Our discovery of SNPs that are highly associated with hepatic GNMT protein expression as well as the "coordinate regulation" of methionine cycle enzyme protein levels provide novel insight into the regulation of this important human liver biochemical pathway.
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Project description:Transcriptomic analysis of 5637 bladder cancer cell line transfected with MAT1A plamid, 48 hours post transfection
2019-06-22 | GSE133123 | GEO
Project description:Liver of MAT1A WT and MAT1A KO mice treated with placebo or SAMe during 8 weeks
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Project description:Although many protein-coding genes have been identified to be aberrantly expressed in hepatocellular carcinoma (HCC), the mechanisms that account for development and progression of HCC remain unclear. In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in mammalian cell biology. Many lncRNAs can result in aberrant expression of gene products that may contribute to cancer biology. In this study, we first identified non-overlapping signatures of a small number of lncRNAs that are aberrantly expressed in human HCC compared with paired peritumoral tissues. Then we used real-time PCR to validate five lncRNAs whose expression was altered in HCC compared with paired peritumoral tissues. Using loss-of-function and gain-of-function approaches, we found that an lncRNA (termed lncRNA-HEIH) plays a key role in cell cycle regulation. We further demonstrated that lncRNA-HEIH bound to enhancer of zeste homolog 2 (EZH2) and that this interaction was required for the repression of EZH2 target genes. Together, these results reveal insights into the molecular regulation mechanisms of HCC cell cycle regulation and lead us to propose that lncRNAs may serve as key regulatory hubs in cancer biology. A ten chip study using total RNA recovered from five separate HCC tissues and five corresponding paired non-tumor samples.
2011-09-04 | E-GEOD-27462 | biostudies-arrayexpress
Project description:We report that 7 of 7 female Gnmt-/- mice developed hepatocellular carcinoma (HCC), the most common form of liver cancer, at the mean age of 16.1 months. In contrast, only one-third (2/6) of male Gnmt-/- mice had HCC, the remaining had either premature death or liver necrosis. Microarray analysis showed that genes involved in the following pathways were deregulated in different stages of tumorigenesis: S-adenosylmethionine (SAM)-dependent methyltransferases, metabolism, signal transduction, cell proliferation, cell adhesion and immune responses. This study reveals that GNMT plays an important role in the prevention of hapatotumorigenesis through regulating DNA methylaiton and oxidative stress signaling pathways. We postulate that GNMT is a stress-responsive protein and its expression may account for the gender difference of the susceptibility to liver cancer. Keywords: Gnmt knockout Liver tissues from wild-type or Gnmt knockout mice at young ages, devoloping dysplasia nodules or HCC were used for RNA extraction and hybridization on Affymetrix microarrays. For 11 weeks old mice, total RNA were mixed in equal proportion from 3 mice.
2008-12-01 | E-GEOD-9809 | biostudies-arrayexpress
Project description:We report that 7 of 7 female Gnmt-/- mice developed hepatocellular carcinoma (HCC), the most common form of liver cancer, at the mean age of 16.1 months. In contrast, only one-third (2/6) of male Gnmt-/- mice had HCC, the remaining had either premature death or liver necrosis. Microarray analysis showed that genes involved in the following pathways were deregulated in different stages of tumorigenesis: S-adenosylmethionine (SAM)-dependent methyltransferases, metabolism, signal transduction, cell proliferation, cell adhesion and immune responses. This study reveals that GNMT plays an important role in the prevention of hapatotumorigenesis through regulating DNA methylaiton and oxidative stress signaling pathways. We postulate that GNMT is a stress-responsive protein and its expression may account for the gender difference of the susceptibility to liver cancer. Keywords: Gnmt knockout
2008-12-01 | GSE9809 | GEO
Project description:Hepatocellular carcinoma (HCC) is a common malignancy with high mortality due to a lack of effective therapies. HCC represents a collection of highly heterogeneous tumor types but a general molecular classification of HCC is lacking. Here, we define three molecular subtypes of HCC that are observed across various independent patient cohorts and profiling platforms. Analysis of the expression signatures indicates that a limited number of pathways and processes drive the clustering of these subtypes. Notably, TGF-beta signaling is a critical factor that distinguishes two subtypes of high-grade tumors, and is associated with early tumor recurrence. Furthermore, both bioinformatics and functional analyses reveal molecular crosstalk between TGF-beta and WNT signaling pathways. These findings suggest that TGF-beta plays a critical role in a subclass of HCC tumors and may enhance WNT pathway activation in the absence of activating mutations in canonical pathway components. This study is an example of how robust molecular subclassification can be used to interrogate molecular abnormalities in the context of human cancer. Experiment Overall Design: Four hepatocellular carcinoma (HCC) cell line samples treated or untreated by TGF-beta
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