Lactate-dependent Transcriptional Regulation Controls Mammalian Eye Morphogenesis [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE202757 | GEO | 2023/06/08
REPOSITORIES: GEO
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Project description:Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.
2023-06-08 | GSE224648 | GEO
Project description:Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.
2023-06-08 | GSE202758 | GEO
Project description:Signal Transducer and Activator of Transcription 3 (STAT3) is considered as an oncogene being constitutively activated in a wide variety of primary human tumours, which often become addicted to its activity. Using primary fibroblasts derived from a knock-in mouse expressing only the constitutively active form STAT3-C as well as STAT3-dependent tumor cell lines MDA-MB468, DU145 and SKBR3, we provide evidence that STAT3 can act as a central regulator of cell metabolism. STAT3C/C MEFs are resistant to apoptosis and senescence and they show reduced mitochondrial activity but activate aerobic glycolysis, as shown by enhanced expression of master regulators of glycolysis such as PDK-1 and HIF-1α, and by increased lactate production, glucose avidity and sensitivity to glycolysis inhibitors. HIF-1α is up-regulated in the STAT3C/C MEFs and is responsible for the glycolytic phenotype. Moreover, inhibition of STAT3 activity in STAT3-addicted tumour cell lines restores mitochondrial activity and down-regulates glycolytic metabolism, preceding the induction of massive apoptosis. Thus, the essential role observed for STAT3 in so many different cancer cell types may be partly explained by its ability to act as a molecular switch of cellular metabolism triggering abnormal cell survival/proliferation. Three biological replicates of MEFs from mice with constitutively active Stat3 are compared to three biological replicates of wild-type MEFs.
2010-11-17 | E-GEOD-21507 | biostudies-arrayexpress
Project description:On a daily basis, we turnover billions of apoptotic cells that are removed by professional and non-professional phagocytes1-10. While characterizing the transcriptional program of phagocytes, we discovered a novel solute carrier family (SLC) gene signature (33 SLC members) that is specifically modified during engulfment of apoptotic cells (efferocytosis) but not during antibody-mediated phagocytosis. When we assessed the functional relevance of these SLCs, we noted robust induction of an aerobic glycolysis program in engulfing phagocytes, initiated by SLC2A1-mediated glucose uptake, and suppression of oxidative phosphorylation program. Interestingly, the different steps of phagocytosis10,11, i.e. smell (‘find-me’ signals / sensing factors released by apoptotic cells), taste (phagocyte- apoptotic cell contact), and ingestion (corpse internalization), activated different molecules to promote this glycolytic process. Further, lactate, a natural by-product of aerobic glycolysis12,13, was released from engulfing phagocytes via SLC16A1, an SLC member activated after corpse uptake. While glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, the lactate released via SLC16A1 influenced the establishment of an anti-inflammatory environment. Collectively, these data reveal a novel SLC program activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake, and that glycolytic byproducts of efferocytosis can also influence other cells in the microenvironment.
2018-11-30 | GSE119273 | GEO
Project description:Previous findings have demonstrated that the NADH/NAD+ ratio has a strong impact on the glycolytic flux in C. glutamicum under anaerobic conditions in the absence of external electron acceptors. During an attempt to rewire anaerobic metabolism to achieve high yield formation of ethanol, we inactivated the malate dehydrogenase and lactate dehydrogenase in a C. glutamicum strain expressing pyruvate decarboxylase and alcohol dehydrogenase, to eliminate formation of the by-products succinate and lactate, respectively. This modification increased the yield of ethanol but had a negative effect on glycolysis, which we found to correlate with an elevated NADH/NAD+ ratio. The pyruvate dehydrogenase (PDH) of C. glutamicum is active under anaerobic conditions, and can potentially exacerbate the negative effect on glycolysis, due to NADH formation. To reduce PDH activity under anaerobic conditions, we decided to replace the gene encoding the E3 subunit of PDH with its Escherichia coli counterpart, as E. coli PDH has been reported to be functional under aerobic conditions only. The resultant strain JS133 produced far less acetate with a further increased ethanol production, however, the glycolytic flux was still low. After observing differences in glycolytic flux for JS133 on glucose and fructose, we speculated that the pentose phosphate pathway (PPP) might be involved in the reduced flux on glucose. To prove this, we deleted the zwf gene, encoding glucose-6-phosphate dehydrogenase, which is the entry point into PPP, and immediately observed a stimulating effect on glycolysis. Subsequent characterization revealed a direct correlation between the intracellular NADH/NAD+ and NADPH/NADP+ ratios under anoxic conditions. Based on these findings we managed to re-channel the metabolism of C. glutamicum successfully towards either to ethanol or D-lactate with 92% and 98% of the theoretical yield respectively, which is the highest yields for D-lactate production thus far reported in the literature.
2020-10-02 | GSE143977 | GEO
Project description:Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated macrophage M2-like phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in patients with breast cancer. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor-macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.
2022-03-09 | GSE189779 | GEO
Project description:Signal Transducer and Activator of Transcription 3 (STAT3) is considered as an oncogene being constitutively activated in a wide variety of primary human tumours, which often become addicted to its activity. Using primary fibroblasts derived from a knock-in mouse expressing only the constitutively active form STAT3-C as well as STAT3-dependent tumor cell lines MDA-MB468, DU145 and SKBR3, we provide evidence that STAT3 can act as a central regulator of cell metabolism. STAT3C/C MEFs are resistant to apoptosis and senescence and they show reduced mitochondrial activity but activate aerobic glycolysis, as shown by enhanced expression of master regulators of glycolysis such as PDK-1 and HIF-1α, and by increased lactate production, glucose avidity and sensitivity to glycolysis inhibitors. HIF-1α is up-regulated in the STAT3C/C MEFs and is responsible for the glycolytic phenotype. Moreover, inhibition of STAT3 activity in STAT3-addicted tumour cell lines restores mitochondrial activity and down-regulates glycolytic metabolism, preceding the induction of massive apoptosis. Thus, the essential role observed for STAT3 in so many different cancer cell types may be partly explained by its ability to act as a molecular switch of cellular metabolism triggering abnormal cell survival/proliferation.
2010-11-17 | GSE21507 | GEO
Project description:Merkel cell polyomavirus (MCPyV) is an etiological agent of Merkel cell carcinoma (MCC), a highly aggressive skin cancer. The MCPyV small tumor antigen (ST) is required for maintenance of MCC and can transform normal cells. To gain insight into cellular perturbations induced by MCPyV ST, we performed transcriptome analysis of normal human fibroblasts with inducible expression of ST. MCPyV ST dynamically alters the cellular transcriptome with increased levels of glycolytic genes, including the monocarboxylate lactate transporter SLC16A1 (MCT1). Extracellular flux analysis revealed increased lactate export reflecting elevated aerobic glycolysis in ST expressing cells. Inhibition of MCT1 activity suppressed the growth of MCC cell lines and impaired MCPyV-dependent transformation of IMR90 cells. Both NF-κB and MYC have been shown to regulate MCT1 expression. While MYC was required for MCT1 induction, MCPyV-induced MCT1 levels decreased following knockdown of the NF-κB subunit RelA, supporting a synergistic activity between MCPyV and MYC in regulating MCT1 levels. Several MCC lines had high levels of MYCL and MYCN but not MYC. Increased levels of MYCL was more effective than MYC or MYCN in increasing extracellular acidification in MCC cells. Our results demonstrate the effects of MCPyV ST on the cellular transcriptome and reveal that transformation is dependent, at least in part, on elevated aerobic glycolysis.
2016-10-28 | GSE79968 | GEO
Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.
2016-03-08 | E-GEOD-76675 | biostudies-arrayexpress
Project description:Cell proliferation is achieved by numerous enzyme reactions. Temperature governs the activity of each enzyme, which overall determines the optimal growth temperature. Synthesizing useful chemicals and fuels utilizes only part of the metabolic pathways, especially the central metabolic pathways such as glycolysis and TCA cycle to metabolize glucose. However, the optimal temperature for the activity of the central metabolic pathways is inconclusive whether it is correlated with the optimal temperature for cell proliferation. Here, we found that Corynebacterium glutamicum wild type increased the metabolic activity to consume glucose under anaerobic (oxygen deprived) conditions at 42.5ºC, in which the cell hardly grows under aerobic conditions. Glucose consumption rate was increased by 24% at 42.5ºC compared to that at the optimal growth temperature of 30.0ºC. Transcriptional analysis showed that gapX gene encoding glycelaldehydre-3-phosphate dehydrogenase, glucokinase gene, and a gene involved in glucose uptake were upregulated at 42.5ºC. Production of fermentative lactate was increased by 69% than that at 30.0ºC, whereas succinate production was decreased by 13%. In addition to several glycolytic enzymes, the activity of pyruvate kinase was increased with increasing the temperature, whereas the activity of phosphoenolpyruvate carboxylase in anapleotic pathway leading to succinate synthesis was decreased. However, a metabolically engineered succinate over-producing strain, in which lactate production was shut off and pyruvate carboxylase encoding gene in another anapleotic pathway was overexpressed, produced 34% higher succinate at 42.5ºC than that at 30.0ºC with increased glucose consumption. This study provides the evidence that the optimal reaction temperature for production of fermentative products can be set beyond upper limit of growth temperature in C. glutamicum, and hence it could be applicable for producing various chemicals and fuels in C. glutamicum under anaerobic conditions and non-growing cell reactions in other microorganisms.
2020-06-23 | GSE123063 | GEO