Transcriptomics on MDA-MB-231 cells adapted to methionine-free medium
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE291735 | GEO | 2025/04/08
REPOSITORIES: GEO
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Project description:The amino acid homocysteine increases in the serum when there is insufficient folic acid or vitamin B12, or with certain mutations in enzymes important in methionine metabolism. Elevated homocysteine is related to increased risk for cardiovascular and other diseases in adults and elevated maternal homocysteine increases the risk for certain congenital defects, especially those that result from abnormal development of the neural crest and neural tube. Experiments with the avian embryo model have shown that elevated homocysteine perturbs neural crest / neural tube migration in vitro and in vivo. While there have been numerous studies of homocysteine-induced changes in gene expression in adult cells, there is no previous report of a homocysteine-responsive transcriptome in the embryonic neural crest. We treated neural crest cells in vitro with exogenous homocysteine in a protocol that induces significant changes in neural crest cell migration. We used microarray analysis and expression profiling to identify 65 transcripts of genes of known function that were altered by homocysteine. The largest set of effected genes (19) included those with a role in cell migration and adhesion. Other major groups were genes involved in metabolism (13); DNA / RNA interaction (11); cell proliferation / apoptosis (10); and transporter / receptor (6). Although the genes identified in this experiment were consistent with prior observations of the effect of homocysteine upon neural crest cell function, none had been identified previously as response to homocysteine in adult cells. Keywords: homocysteine ● microarray ● expression profiling ● embryo ● neural crest
2007-01-26 | GSE6868 | GEO
Project description:The industrial solvent trichloroethylene (TCE) produces a marked formic aciduria in male and female F344 rats and in male C57Bl mice following single or multiple dosing. The two major metabolites of TCE formed by cytochromes P450 metabolism also produce formic aciduria. The quantity of formic acid excreted was about 2-fold higher following trichloroacetic acid (TCA) compared to trichloroethanol (TCE-OH) or TCE, at similar doses of 16mg/kg/day for 3 days. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE, completely prevented the formic aciduria but had no effect on formic acid excretion produced by TCA, suggesting TCA is the proximate metabolite producing this response. Metabolism of formic acid is largely controlled by the vitamin B12 –dependent methionine salvage pathway. Transcriptomic analysis on the liver of rats dosed with 16mg/kg/day TCE for three days when compared to control liver showed nine differentially expressed genes, of particular interest was the down regulation of LMBRD1 involved in the conversion of vitamin B12 into one of two molecules, methylcobalamin (CH3Cbl) or S-adenosylcobalamin (AdoCbl). Administration of CH3Cbl or hydroxocobalamin for 3 days to rats given a single dose of TCE, lead to a reduction in formic acid in their urine. Similarly, rats given TCE followed by L-methionine for 3 days excreted less formic acid in their urine. These findings suggest an effect on the vitamin B12 –dependent methionine salvage pathway. This was supported by the finding that hepatic methionine synthase, which converts homocysteine to methionine, was inhibited following three large daily dose of TCE. We propose that TCE metabolites interact with the vitamin B12 -dependent methionine salvage pathway leading to tetrahydrofolate deficiency and increased excretion of formic acid in rat urine.
2020-11-20 | GSE122664 | GEO
Project description:Purpose: RNAseq analysis of hPSC undergoing in vitro hepatic differentiation, to validate proper differentiation at different times of differentiation (D0 to D21)
2019-06-13 | GSE132606 | GEO
Project description:Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent versus methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generic rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, the methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but trigger different outcomesin methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and tight junctions in the cellular response to methionine stress in melanoma.
2023-05-03 | GSE225945 | GEO
Project description:Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent versus methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generic rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, the methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of s-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but trigger different outcomesin methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and tight junctions in the cellular response to methionine stress in melanoma.
2023-05-03 | GSE225944 | GEO
Project description:Rationale: Low B12 has been shown to play an important role in the prediction of metabolic risk, but its significance and mechanism in the development of adiposity and adipose tissue dysfunction is largely unknown. Objective: To investigate the role of B12 and folic acid in the development of adipocyte dysfunction. Methods and Results: Microarray analysis of human adipocytes (CHUB-S7 cell line) cultured and differentiated in customised media with varying concentrations of B12 and folic acid led to the identification of two important pathways: cholesterol synthesis and unfolded protein response (UPR). Adipocytes cultured in media with low B12 (150 pmol/L) or no B12 had increased intracellular total cholesterol, higher secreted homocysteine levels, induced UPR and reduced glucose uptake capacity compared to adipocytes cultured in normal media with higher B12. The folate concentrations had either no or little effect on the measured functions. Further analysis of these adipocytes for overall DNA methylation showed that the promoter regions of sterol regulatory element-binding transcription factor 1 (SREBF1) and low density lipoprotein receptor (LDLR) were hypomethylated in the low and no B12 conditions. The SREB proteins (SREBP1 and 2) and mRNA expressions (SREBF1 and LDLR) were also increased in the same conditions. Conclusion: The data suggest that low B12 can lead to adipocyte dysfunction by inducing excess cholesterol biosynthesis, homocysteine production and induction of UPR and overall adipocyte dysfunction. Both of these pathways and adipocyte dysfunction play a significant role in the development of cardiovascular diseases. Independent replicate samples of the human adipocyte cell line CHUB-S7 were treated with four different concentrations of B12 and folate.
2012-12-30 | E-GEOD-43166 | biostudies-arrayexpress
Project description:Rationale: Low B12 has been shown to play an important role in the prediction of metabolic risk, but its significance and mechanism in the development of adiposity and adipose tissue dysfunction is largely unknown. Objective: To investigate the role of B12 and folic acid in the development of adipocyte dysfunction. Methods and Results: Microarray analysis of human adipocytes (CHUB-S7 cell line) cultured and differentiated in customised media with varying concentrations of B12 and folic acid led to the identification of two important pathways: cholesterol synthesis and unfolded protein response (UPR). Adipocytes cultured in media with low B12 (150 pmol/L) or no B12 had increased intracellular total cholesterol, higher secreted homocysteine levels, induced UPR and reduced glucose uptake capacity compared to adipocytes cultured in normal media with higher B12. The folate concentrations had either no or little effect on the measured functions. Further analysis of these adipocytes for overall DNA methylation showed that the promoter regions of sterol regulatory element-binding transcription factor 1 (SREBF1) and low density lipoprotein receptor (LDLR) were hypomethylated in the low and no B12 conditions. The SREB proteins (SREBP1 and 2) and mRNA expressions (SREBF1 and LDLR) were also increased in the same conditions. Conclusion: The data suggest that low B12 can lead to adipocyte dysfunction by inducing excess cholesterol biosynthesis, homocysteine production and induction of UPR and overall adipocyte dysfunction. Both of these pathways and adipocyte dysfunction play a significant role in the development of cardiovascular diseases.
2012-12-30 | GSE43166 | GEO
Project description:Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood, except for the observation that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We found that replacing methionine with homocysteine generally induced hypomethylation in gene promoters. We isolated nuclear proteins and submitted it for tandem mass tag (TMT) proteomics. This analysis revealed that several proteins involved in the mitochondrial integrated stress response (ISR) were upregulated in response to the replacement of methionine to homocysteine in both cell lines, but to a much greater degree in the methionine dependent cell line. Consistent with the ISR signature, a proteomic analysis of a subcellular fraction enriched for mitochondrial content revealed a strong enrichment for proteins involved in oxidative phosphorylation. Analysis of cellular bioenergetics confirmed that homocysteine induces a decrease in ATP production from oxidative phosphorylation and glycolysis, but to a similar extent in methionine dependent and methionine independent cells. The mitochondrial integrated stress response shared a signature with ferroptosis. Methionine dependent cells displayed a strong ferroptotic signature, which was decreased by half in methionine independent cells. Consistent with ferroptosis, malonaldehyde was increased in methionine independent cells grown in homocysteine, and viability could be rescued with the inhibitor ferrostatin. Therefore, we propose that methionine stress induces ferroptotic cell death in methionine dependent cancer cells.
2023-03-07 | MSV000091423 | MassIVE
Project description:We report the change in gene expression in rat liver post chronic sleep restriction. Rats were sleep restricted by for 5 days by forced activity protocol. We found changes in genes related to NAD metabolism (Nampt), TCA cycle (Acly) and methionine metabolism (Msrb2 and Mtr)
2019-01-24 | GSE94026 | GEO
Project description:Exposure to adverse early-life environment (AME) increases the incidence of developing adult-onset non-alcoholic fatty liver disease (NAFLD). DNA methylation has been postulated to link AME and late-onset diseases. The objective was to investigate whether and to what extent hepatic DNA methylome was perturbed prior to the development of NAFLD in offspring exposed to AME in mice. AME constituted maternal western diet and late-gestational stress. Male offspring livers at birth (d0) and weaning (d21) were used for evaluating DNA methylome and transcriptome using reduced representation of bisulfite sequencing and RNA-seq, respectively. We found AME caused 5,879 differentially methylated regions (DMRs) and zero differentially expressed gene (DEG) at d0, and 2,970 and 123, respectively at d21. Majority of the DMRs were distal from gene transcription start sites and did not correlate with DEGs. The DEGs at d21 were significantly en-riched in GO biological processes characteristic of liver metabolic functions. In conclusion, AME drove changes in hepatic DNA methylome which preceded perturbations in the hepatic metabolic transcriptome, which preceded the onset of NAFLD. We speculate that subtle impacts in dynamic enhancers lead to long-range regulatory changes that manifest over time as gene network alter-nations to increase the incidence of NAFLD later in life.
2023-05-23 | GSE232811 | GEO