Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1026611 | ENA |
REPOSITORIES: ENA
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Project description:Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines, and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, AICAR, followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the SHMT1/2 inhibitor - SHIN1, and by AICAR supplementation. Mechanistically, the metabolically-driven differentiation is independent of nucleotide sensing through mTORC1 and AMPK, and is instead mediated by protein kinase C (PKC). Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate-deficiency induced anemia.
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2021-04-17 | GSE168099 | GEO
Project description:Cell cycle and metabolism are two major outputs controlled by circadian rhythm in many organisms. Here we show that the three processes were linked through inosine 5'-phosphate dehydrogenase (impdh), a rate-limiting enzyme in de novo purine synthesis. We using adult zebrafish as a model system,we applied a genome-wide transcriptome approach that allowed us to investigate circadian gene expression. The whole-genome transcriptome profiles of adult brain in time-series were assayed on Agilent zebrafish microarrays. We used a similar statistical method to identify zebrafish circadian genes (ZCOG) as our previous study in larval zebrafish. Three isoforms of impdh show strong circadian oscillations in different tissues of zebrafish. impdh1a contributes to the ocular development and pigment synthesis, impdh2 promotes and impdh1b delays the development. By limiting the GTP required by DNA synthesis, impdh2 contributes to the daily rhythm of S phase in cell cycle. Multiple enzymes in the de novo purine synthesis pathway show the same circadian oscillations with peaks similar to impdh2. The circadian expression of this pathway is conserved in mouse liver. In summary, we show that the circadian regulation of de novo purine synthesis that supplies crucial building blocks for DNA replication is critical for gating cell cycle in circadian rhythm. Adult zebrafish were sacrificed and dissected at 4h intervals starting at CT0 in both LD and DD conditions for 12 time points. Total RNA of individual zebrafish brain was extracted using Trizol (Invitrogen, Carlsbad, CA) according to the manufacturerM-bM-^@M-^Ys instruction. Microarrays were manufactured by Agilent Technologies (Agilent Technologies, Palo Alto, CA), containing 43,603 probes for zebrafish whole-genome transcriptional profiling.
2013-10-01 | E-GEOD-51277 | biostudies-arrayexpress
Project description:Cell cycle and metabolism are two major outputs controlled by circadian rhythm in many organisms. Here we show that the three processes were linked through inosine 5'-phosphate dehydrogenase (impdh), a rate-limiting enzyme in de novo purine synthesis. We using adult zebrafish as a model system,we applied a genome-wide transcriptome approach that allowed us to investigate circadian gene expression. The whole-genome transcriptome profiles of adult brain in time-series were assayed on Agilent zebrafish microarrays. We used a similar statistical method to identify zebrafish circadian genes (ZCOG) as our previous study in larval zebrafish. Three isoforms of impdh show strong circadian oscillations in different tissues of zebrafish. impdh1a contributes to the ocular development and pigment synthesis, impdh2 promotes and impdh1b delays the development. By limiting the GTP required by DNA synthesis, impdh2 contributes to the daily rhythm of S phase in cell cycle. Multiple enzymes in the de novo purine synthesis pathway show the same circadian oscillations with peaks similar to impdh2. The circadian expression of this pathway is conserved in mouse liver. In summary, we show that the circadian regulation of de novo purine synthesis that supplies crucial building blocks for DNA replication is critical for gating cell cycle in circadian rhythm.
2013-10-01 | GSE51277 | GEO
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Project description:In the McSC lineage in zebrafish, Aldh2 activity is an important source of formate through its metabolism of its substrate formaldehyde. This formate is required as input into the folate cycle, in particular de novo purine biosynthesis. This scRNA-seq experiment was conducted to investigate the global effects of Aldh2 inhibition on the transcriptomes of isolated McSCs.
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Project description:Defects in homocysteine and folate metabolism are associated with increased risks for neural tube and congenital heart defects, cardiovascular disease and stroke, cancers, and neurodegeneration. In many but not all cases, dietary supplementation with folate significantly reduces the severity and incidence of these conditions. Common polymorphisms modulate these metabolic pathways and disease risks, but do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test whether other pathways contribute to disease pathogenesis, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and translated to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting an interplay between homocysteine and folate metabolism and cholesterol metabolism. Absence of measurable changes in global methylation patterns or amelioration of effects with supplementation with an alternative methyl donor suggest that dietary folate perturbations do not act through large-scale or general changes in methylation. These results suggest that homeostatic responses in cholesterol metabolism contribute to the beneficial effects of dietary folate supplementation. Keywords: time course, stress response, diet, genetic, homeostasis
2008-08-27 | GSE9242 | GEO
Project description:Morrison1989 - Folate Cycle
The model describes the folate cycle
kinetics in breast cancer cells.
This model is described in the article:
Folate cycle kinetics in
human breast cancer cells.
Morrison PF, Allegra CJ.
J. Biol. Chem. 1989 Jun; 264(18):
10552-10566
Abstract:
A mathematical description of polyglutamated folate kinetics
for human breast carcinoma cells (MCF-7) has been formulated
based upon experimental folate, methotrexate (MTX), purine, and
pyrimidine pool sizes as well as reaction rate parameters
obtained from intact MCF-7 cells and their enzyme isolates. The
schema accounts for the interconversion of highly
polyglutamated tetrahydrofolate, 5-methyl-FH4, 5-10-CH2FH4,
dihydrofolate (FH2), 10-formyl-FH4 (FFH4), and 10-formyl-FH2
(FFH2), as well as formation and transport of the MTX
polyglutamates. Inhibition mechanisms have been chosen to
reproduce all observed non-, un-, and pure competition
inhibition patterns. Steady state folate concentrations and
thymidylate and purine synthesis rates in drug-free intact
cells were used to determine normal folate Vmax values. The
resulting average-cell folate model, examined for its ability
to predict folate pool behavior following exposure to 1 microM
MTX over 21 h, agreed well with the experiment, including a
relative preservation of the FFH4 and CH2FH4 pools. The results
depend strongly on thymidylate synthase (TS) reaction
mechanism, especially the assumption that MTX di- and
triglutamates inhibit TS synthesis as greatly in the intact
cell as they do with purified enzyme. The effects of cell cycle
dependence of TS and dihydrofolate reductase activities were
also examined by introducing G- to S-phase activity ratios of
these enzymes into the model. For activity ratios down to at
least 5%, cell population averaged folate pools were only
slightly affected, while CH2FH4 pools in S-phase cells were
reduced to as little as 10% of control values. Significantly,
these folate pool dynamics were indicated to arise from both
direct inhibition by MTX polyglutamates as well as inhibition
by elevated levels of polyglutamated FH2 and FFH2.
Note: two flow BCs were converted into two downstream
concentration BCs, thus removing the GAR and dUMP state
variables. This dropped the number of ODEs from 21 to 19.
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2024-09-02 | BIOMD0000000018 | BioModels