Low pH controls MondoA genome-wide binding.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125089 | GEO | 2019/01/23
REPOSITORIES: GEO
Similar Datasets
Project description:MondoA and its transcriptional target thioredoxin-interacting protein (TXNIP) constitute a regulatory loop that senses glycolytic flux and controls glucose availability. Cellular stress also triggers MondoA activity and TXNIP expression. To understand how MondoA integrates glucose and stress signals, we studied its activation by acidosis. We found that acidosis drives mitochondrial ATP (mtATP) synthesis. The subsequent export of mtATP from mitochondria via adenine-nucleotide transporter and voltage-dependent anion channel, and the enzymatic activity of mitochondria-bound hexokinase results in the production of glucose-6-phosphate (G6P), a known activator of MondoA transcriptional activity. MondoA localizes to the outer-mitochondrial membrane (OMM), and in response to G6P, shuttles to the nucleus and activates transcription. Our data suggests that MondoA is a required feature of a glucose- and mtATP-dependent, OMM-localized signaling center. We propose MondoA functions as a coincidence detector and its ability to sense glucose and cellular stress is coupled to the concerted production of G6P.
2019-01-23 | GSE117622 | GEO
Project description:BACKGROUND: Protein synthesis is regulated by the availability of amino acids, the engagement of growth factor signaling pathways and ATP levels sufficient to support translation. Crosstalk between these inputs is extensive, yet other regulatory mechanisms remain to be characterized. For example, the translation initiation inhibitor Rocaglamide A (RocA) induces Thioredoxin Interacting Protein (TXNIP). TXNIP is a negative regulator of glucose uptake, thus its induction by RocA links translation to the availability of glucose. MondoA is the principal regulator of glucose-induced transcription and its activity is triggered by the glycolytic intermediate, glucose 6-phosphate (G6P). MondoA responds to G6P generated by cytoplasmic glucose and mitochondrial ATP (mtATP), suggesting a critical role in the cellular response to these energy sources. TXNIP expression is entirely dependent on MondoA, therefore, we investigated how protein synthesis inhibitors impact its transcriptional activity. METHODS: We investigated how translation regulates MondoA activity using cell line models and loss-of-function approaches. We examined how protein synthesis inhibitors effect gene expression and metabolism using RNA-sequencing and metabolomics, respectively. The biological impact of RocA was evaluated using both cell line models and Patient-Derived Xenograft Organoid models. RESULTS: We discovered that multiple protein synthesis inhibitors, including RocA, increase TXNIP expression in a manner that depends on MondoA, a functional electron transport chain and mtATP synthesis. Furthermore, RocA increases mtATP and G6P levels and TXNIP induction depends on interactions between the Voltage-Dependent Anion Channel (VDAC) and hexokinase, which generates G6P. RocA treatment impacts the regulation of ~1200 genes and ~250 of those genes are MondoA-dependent. RocA treatment is cytotoxic to Triple Negative Breast Cancer cell lines and shows preferential cytotoxicity against ER- patient-derived breast cancer models. Finally, RocA-driven cytotoxicity is partially-dependent on MondoA or TXNIP. CONCLUSION: Our data suggest that protein synthesis inhibitors rewire metabolism, resulting in an increase in mtATP and G6P, the latter driving MondoA-dependent transcriptional activity. Further, MondoA is a critical component of the cellular transcriptional response to RocA. Our functional assays suggest that RocA or similar translation inhibitors may show efficacy against ER- tumors and that the levels of MondoA and TXNIP should be considered when exploring these potential treatment options.
2020-12-07 | GSE153499 | GEO
Project description:Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. To identify novel candidates for targeted treatment of childhood ALL, we performed a comprehensive transcriptome analysis yielding a set of genes specifically overexpressed in ALL. Among them we identified MondoA - a transcription factor regulating glycolysis in response to glucose availability. Here, we confirm that MondoA is highly overexpressed ALL, whereas the MondoA paralog, MondoB, is not expressed. Expression studies revealed that MondoA is not regulated by glucose availability in leukemia cells, but by the presence of lactate. An in silico MondoA promoter analysis identified two methylation-prone CpG-islands and four conserved binding sites for runt-related transcription factor 1 (RUNX1). In fact, MondoA and RUNX1 are significantly coexpressed in leukemia and experimental blockage of DNA methylation leads to a further induction of MondoA. In addition, using microarray profiling, gene-set enrichment analysis and RNA interference we provide for the first time evidence that MondoA expression not only increases glucose catabolism, but also maintains a more immature ALL phenotype, which is associated with enhanced survival and clonogenicity of leukemia cells. These data hint to an important contribution of MondoA to leukemia aggressiveness validating MondoA as an attractive candidate for targeted treatment of ALL. Two nonsense shRNA expressing control Nalm6 clones and three MondoA shRNA expressing Nalm6 clones were subjected to microarray analysis.
2012-07-31 | E-GEOD-33967 | biostudies-arrayexpress
Project description:To determine the contibution of the transcription factor MondoA to 2-deoxyglucose-induced transcription expression analysis was carried out in control and MondoA knockdown cells HA1ER cells are human embryonic kidney cells transformed with hTERT, SV40 Early region and activated H-Ras Keywords: cell type comparision, genetic modification HA1ER cells, Control (NS) or MondoA knockdown (M2), were starved for glucose overnight and then treated with 2-deoxyglucose for 3 hours
2008-04-24 | E-GEOD-11242 | biostudies-arrayexpress
Project description:Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD-/- mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD-/- mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1a (Pgc-1a) and decreased peroxisome proliferator-activated receptor alpha (Ppar a) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD-/- mice in both conditions,suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD-/- mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD-/- mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD-/- mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD-/- mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD-/- mice, was mainly due to enhanced peripheral glucose uptake. Conclusion: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation. Total RNA obtained from Liver ( 20 samples) , where comparing 4 groups, consisting out of 5 biological replicates, all groups where fasted for 12 hrs, and half of them where injected with LPS ( 100ug/20gr BW) or vehicle
2012-04-25 | E-GEOD-37546 | biostudies-arrayexpress
Project description:Cellular acidosis triggers MondoA transcriptional activity by driving mitochondrial ATP production
| PRJNA482669 | ENA
Project description:The glucose-sensing Mondo pathway regulates expression of metabolic genes in mammals. Here, we have revealed an unexpected role of this pathway in vertebrate embryonic development. We characterized Mondo pathway function in the zebrafish and showed that knock-down of mondoa impaired the early morphogenetic movement of epiboly in zebrafish embryos. Expression of nsdhl , an enzyme of cholesterol and pregnenolone synthesis, was strongly reduced in these embryos. Loss of Nsdhl function likewise impaired epiboly and led to microtubule cytoskeleton defects in the embryo, similar to MondoA loss of function. Both epiboly and microtubule cytoskeleton defects were partially restored by pregnenolone treatment. Gene disruption of mondoa perturbed epiboly with only partial penetrance, likely due to compensatory changes in the expression of cholesterol/steroid metabolism genes. Collectively, our results show a novel role for MondoA in the regulation of early vertebrate development, connecting glucose, cholesterol and steroid hormone metabolism with early embryonic cell movements.
2020-09-11 | GSE144349 | GEO
Project description:The glucose-sensing Mondo pathway regulates expression of metabolic genes in mammals. Here, we have revealed an unexpected role of this pathway in vertebrate embryonic development. We characterized Mondo pathway function in the zebrafish and showed that knock-down of mondoa impaired the early morphogenetic movement of epiboly in zebrafish embryos. Expression of nsdhl , an enzyme of cholesterol and pregnenolone synthesis, was strongly reduced in these embryos. Loss of Nsdhl function likewise impaired epiboly and led to microtubule cytoskeleton defects in the embryo, similar to MondoA loss of function. Both epiboly and microtubule cytoskeleton defects were partially restored by pregnenolone treatment. Gene disruption of mondoa perturbed epiboly with only partial penetrance, likely due to compensatory changes in the expression of cholesterol/steroid metabolism genes. Collectively, our results show a novel role for MondoA in the regulation of early vertebrate development, connecting glucose, cholesterol and steroid hormone metabolism with early embryonic cell movements.
2020-09-11 | GSE134778 | GEO
Project description:Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. To identify novel candidates for targeted treatment of childhood ALL, we performed a comprehensive transcriptome analysis yielding a set of genes specifically overexpressed in ALL. Among them we identified MondoA - a transcription factor regulating glycolysis in response to glucose availability. Here, we confirm that MondoA is highly overexpressed ALL, whereas the MondoA paralog, MondoB, is not expressed. Expression studies revealed that MondoA is not regulated by glucose availability in leukemia cells, but by the presence of lactate. An in silico MondoA promoter analysis identified two methylation-prone CpG-islands and four conserved binding sites for runt-related transcription factor 1 (RUNX1). In fact, MondoA and RUNX1 are significantly coexpressed in leukemia and experimental blockage of DNA methylation leads to a further induction of MondoA. In addition, using microarray profiling, gene-set enrichment analysis and RNA interference we provide for the first time evidence that MondoA expression not only increases glucose catabolism, but also maintains a more immature ALL phenotype, which is associated with enhanced survival and clonogenicity of leukemia cells. These data hint to an important contribution of MondoA to leukemia aggressiveness validating MondoA as an attractive candidate for targeted treatment of ALL.
2012-08-01 | GSE33967 | GEO
Project description:Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD-/- mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD-/- mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1a (Pgc-1a) and decreased peroxisome proliferator-activated receptor alpha (Ppar a) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD-/- mice in both conditions,suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD-/- mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD-/- mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD-/- mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD-/- mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD-/- mice, was mainly due to enhanced peripheral glucose uptake. Conclusion: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation.
2012-04-26 | GSE37546 | GEO