M6A modification regulates cell proliferation via reprogramming the balance between glycolysis and pentose phosphate pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1087349 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28332126_1.fastq.gz | Fastqsanger.gz | |||
| SRR28332126_2.fastq.gz | Fastqsanger.gz | |||
| SRR28332127_1.fastq.gz | Fastqsanger.gz | |||
| SRR28332127_2.fastq.gz | Fastqsanger.gz | |||
| SRR28332130_1.fastq.gz | Fastqsanger.gz |
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Project description:N6-methyladenosine (m6A) stands as the predominant modification in eukaryotic mRNA and is involved in various biological functions. Aberrant m6A has been implicated in abnormal cellular phenotypes, including defects in stem cell renewal and tumorigenesis. However, the precise effects of m6A on cell proliferation and the underlining mechanism of metabolic gene regulation remain incompletely understood. Here, we established a cellular environment with low-m6A levels and observed a severe impairment of cell proliferation. Mechanistic studies revealed that the depletion of m6A on TIGAR mRNA led to increased expression, subsequently inhibiting glycolysis while promoting the pentose phosphate pathway (PPP). A genome-wide CRISPR-Cas9 screen identified extensive genes involved in cell proliferation that are affected by m6A modification, with G6PD emerging as a key regulator. Integration of gene expression and survival data from LIHC patients suggested specific subsets with elevated G6PD expression may exhibit enhanced responsiveness to tumor growth inhibition through m6A suppression. Our findings elucidate the critical role of m6A in cellular metabolic regulation, particularly in the metabolic reprogramming of cell proliferation, offering new insight for cancer therapy.
2025-03-22 | GSE261509 | GEO
Project description:During early pregnancy, glucose is essential for the uterine epithelium and the developing embryo. In cows, studies have shown that progesterone increases the secretion of glucose into the uterine lumen. Nevertheless, how progesterone affects glucose metabolism in the uterine epithelium has been sparsely investigated. Therefore, our objective was to investigate how progesterone influences glucose metabolism in immortalized bovine uterine epithelial (BUTE) cells. Progesterone treatment (10 μM) increased glucose consumption. To gain a more global picture of the effects of progesterone, RNAseq was performed after BUTE cells were treated with vehicle (DMSO) or 10 μM for 24 hours. KEGG analysis indicated that progesterone altered genes associated with metabolic pathways and glutathione metabolism. Manually examining genes unique to specific glucose metabolic pathways identified an increase in the rate-limiting enzyme in the pentose phosphate pathway—glucose-6-phosphate dehydrogenase. Functionally, a major product of the pentose phosphate pathway is NADPH, and progesterone treatment increased NADPH concentrations in BUTE cells. In cows, immunohistochemistry confirmed that glucose-6-phosphate dehydrogenase levels were higher in the uterine epithelium in the luteal phase when progesterone concentrations are high. In conclusion, progesterone increased glucose-6-phosphate dehydrogenase expression and metabolism via the pentose phosphate pathway in the bovine uterine epithelium. This metabolism could provide substrates for cell proliferation, molecules to be secreted into the uterine lumen that supports embryonic development, or maintain reduction/oxidation balance in the uterine epithelium.
2024-10-09 | GSE269076 | GEO
Project description:Oxygen fluctuation during tissue remodeling imposes a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastomas are believed to possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. To identify adaptive response mechanism, we compared the effects of acute and chronic hypoxia versus oxygenation on stem-like glioblastoma (GS) cells. GS cell lines were established and propagated either under normoxia (21% O2) or hypoxia (1% O2) and subsequently exposed to acute normoxia or hypoxia, respectively. Gene expression profiling revealed that acute hypoxia predominantly induced metabolic pathways and cell cycle arrest, whereas chronic hypoxia activated neurodevelopmental processes. In particular, we found increased expression of glycolytic enzymes, especially of the preparatory phase of glycolysis, under acute hypoxia, whereas pentose phosphate pathway (PPP) enzymes were downregulated. The opposite was found for acute oxygenation of hypoxic GS cells. Findings were confirmed by qPCR and immunoblot analyses. Despite downregulation by hypoxia, expression of PPP enzymes is increased in GBMs compared to normal brain, whereas expression of hypoxia-inducible enzymes of the parallel preparatory phase of glycolysis is decreased. Immunohistochemistry revealed strong staining for PPP enzymes in the bulk of GBM tissue, especially in highly proliferative areas, but not in pseudopalisading (hypoxic) cells. Glycolytic enzymes displayed an inverse pattern. Mass spectrometric analysis using [1,2-13C2]-D-glucose showed reduced glucose flux through the PPP under hypoxia in favor of flux through glycolysis. Acute and chronic hypoxia increased cell migration but reduced proliferation, whereas normoxia had opposite effects. Our findings extend Warburg’s observations by showing that in most tumor cells the PPP, which supplies metabolites for biomass production, is favored over the parallel preparatory phase of glycolysis, but is suppressed under acute severe hypoxia, causing a switch to direct glycolysis to protect against hypoxic stress.
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Project description:PCNA is an essential protein in all cells with multiple well-known function in DNA replication and DNA repair. Recently, PCNA was shown to be involved in regulation of cellular signalling and central carbon metabolism via stabilizing the metabolic enzymes ENO1 and 6PGD. Furthermore, ATX-101, a PCNA targeting peptide currently in Phase II, was shown to reduce metabolite pools in the glycolysis and the pentose phosphate pathway (PPP) in multiple haematological cells. Here integrated analysis of signalome and metabolome data from multiple myeloma (MM) cells reveals large effects of ATX-101 on signalling, metabolism and red-ox regulation. The sensitivity to ATX-101 varied between the eight MM cell lines studied and a metabolic shift was detected in the sensitive cell lines. These cell lines were characterized by low endogenous levels of the redox metabolites NAD+, NADH and GSH. Interestingly, 11 proteins were pulled down from untreated cells from the sensitive cell lines while not from 9 other cancer cell lines or primary monocytes from three donors. These proteins could be potential biomarkers for MM cells with low red-ox capacity and hypersensitivity for inhibitors of glycolysis or the PPP.
2024-11-25 | PXD033510 | Pride
Project description:Messiha2013 - combined glycolysis and pentose phosphate pathway model
BIOMD0000000502
and MODEL1303260018
are combined to examine the response to oxidative stress.
This model is described in the article:
Enzyme characterisation and kinetic modelling of pentose phosphate pathway in yeast.
Hanan L. Messiha, Edward Kent, Naglis Malys, Kathleen M. Carroll, Pedro Mendes, Kieran Smallbone
PeerJ PrePrints 1:e146v2
Abstract:
We present the quantification and kinetic characterisation of the enzymes of the pentose phosphate pathway in Saccharomyces cerevisiae. The data are combined into a mathematical model that describes the dynamics of this system and allows for the predicting changes in metabolite concentrations and fluxes in response to perturbations. We use the model to study the response of yeast to a glucose pulse. We then combine the model with an existing glycolysis one to study the effect of oxidative stress on carbohydrate metabolism. The combination of these two models was made possible by the standardized enzyme kinetic experiments carried out in both studies. This work demonstrates the feasibility of constructing larger network models by merging smaller pathway models.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000503
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
2024-09-02 | BIOMD0000000503 | BioModels
Project description:PCNA is an essential protein in all cells with multiple well-known function in DNA replication and DNA repair. Recently, PCNA was shown to be involved in regulation of cellular signalling and central carbon metabolism via stabilizing the metabolic enzymes ENO1 and 6PGD. Furthermore, ATX-101, a PCNA targeting peptide currently in Phase II, was shown to reduce metabolite pools in the glycolysis and the pentose phosphate pathway (PPP) in multiple haematological cells. Here integrated analysis of signalome and metabolome data from multiple myeloma (MM) cells reveals large effects of ATX-101 on signalling, metabolism and red-ox regulation. The sensitivity to ATX-101 varied between the eight MM cell lines studied and a metabolic shift was detected in the sensitive cell lines. These cell lines were characterized by low endogenous levels of the redox metabolites NAD+, NADH and GSH. Interestingly, 11 proteins were pulled down from untreated cells from the sensitive cell lines while not from 9 other cancer cell lines or primary monocytes from three donors. These proteins could be potential biomarkers for MM cells with low red-ox capacity and hypersensitivity for inhibitors of glycolysis or the PPP.
2024-11-25 | PXD033531 | Pride
Project description:Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and hence represent potential targets for anti-bacterial strategies. Here, we addressed the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. We have previously shown that this intracellular bacterial pathogen used gluconeogenesis to metabolize host-derived nutrients in the cytosolic compartment of infected macrophages. Francisella species, which lacks the oxidative branch of the PPP, are equipped with all the genes of the non-oxidative branch (i.e. tktA, tal, rpiA and rpe, encoding transketolase, transaldolase, ribose-phosphate isomerase and ribulose phosphate epimerase, respectively). The involvement of the PPP in the early stage of intracellular life cycle of F. novicida was first demonstrated with the study of PPP inactivation mutants. Indeed, inactivation of tktA, rpiA or rpe genes, severely impaired intramacrophagic multiplication during the first 24–hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular bacterial multiplication. To get further insight into the links between the PPP and other metabolic networks of the bacterium, we next performed a thorough proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections with glycolysis, tricarboxylic acid cycle and other metabolic pathways, such as fatty acid degradation and sulfur metabolism. Hence, our study highlights how, by its multiple connections with other metabolic pathways, PPP is instrumental to Francisella pathogenesis and growth in its intracellular niche.
2021-07-27 | PXD023550 | Pride
Project description:Kerkhoven2013 - Glycolysis and Pentose Phosphate Pathway in T.brucei - MODEL B
There are six models (Model A, B, C, C-fruc, D, D-fruc) described in the paper. Model A ( BIOMD0000000513
) is the model developed originally by Achar et al. (2012) ( BIOMD0000000428
), which describes glycolysis in T.brucei. This glycolysis model is extended to include pentose phosphate pathway (PPP), which is Model B (( BIOMD0000000514
). Model B is further extended to include glycosomal ribokinase, leading to Model C ( BIOMD0000000510
). Model D ( BIOMD0000000511
) is again an extension of Model B, which includes an ATP:ADP antiporter. Model C-fruc ( BIOMD0000000515
) and Model D-fruc ( BIOMD0000000516
) are extensions of Model C and D, respectively, which includes fructose transporter and its subsequent utilizing reactions. This model correspond to Model B of the paper.
This model is described in the article:
Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei.
Kerkhoven EJ, Achcar F, Alibu VP, Burchmore RJ, Gilbert IH, Trybiło M, Driessen NN, Gilbert D, Breitling R, Bakker BM, Barrett MP.
PLoS Comput Biol. 2013 Dec;9(12):e1003371.
Abstract:
Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000514
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000514 | BioModels
Project description:Messiha2013 - Pentose phosphate pathway model
This model describes the dynamic behaviour of the pentose phosphate pathway with the inclusion of various enzymes involved in the pathway. The model's predictions are compared with experimental observations of transient metabolite concentrations following a glucose pulse.
This model is described in the article:
Enzyme characterisation and kinetic modelling of pentose phosphate pathway in yeast.
Hanan L. Messiha, Edward Kent, Naglis Malys, Kathleen M. Carroll, Pedro Mendes, Kieran Smallbone
PeerJ PrePrints 1:e146v2
Abstract:
We present the quantification and kinetic characterisation of the enzymes of the pentose phosphate pathway in Saccharomyces cerevisiae. The data are combined into a mathematical model that describes the dynamics of this system and allows for the predicting changes in metabolite concentrations and fluxes in response to perturbations. We use the model to study the response of yeast to a glucose pulse. We then combine the model with an existing glycolysis one to study the effect of oxidative stress on carbohydrate metabolism. The combination of these two models was made possible by the standardized enzyme kinetic experiments carried out in both studies. This work demonstrates the feasibility of constructing larger network models by merging smaller pathway models.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000502
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000502 | BioModels
Project description:Here, gene profiles in rat spermatogonial stem cell lines are compared to publicly available mouse, monkey and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2 and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were over-represented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gclc, Gclm, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells and ferroptosis inhibitors counteracted the cysteine starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.
2020-12-17 | GSE163302 | GEO