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Project description:To investigate the associated with abnormal DNA demethylation and neural tube defects (NTDs) with folate deficiency, we etablished mouse embryonic stem cells (mESCs) Sv/129 in folate-deficiency-treated.
2022-09-20 | GSE204872 | GEO
Project description:To investigate the associated with abnormal DNA demethylation and neural tube defects (NTDs) with folate deficiency, we etablished mouse embryonic stem cells (mESCs) Sv/129 in folate-deficiency-treated.
2022-09-20 | GSE204870 | GEO
Project description:To investigate the associated with the levels of DNA demethylation and neural tube defects (NTDs) with folate deficiency, we etablished mouse embryonic stem cells (mESCs) Sv/129 in folate-deficiency-treated. We then performed gene expression profiling analysis using data obtained from RNA-seq of the cell model.
2022-09-20 | GSE204871 | GEO
Project description:To investigate the associated with DNA demethylation and neural tube defects (NTDs) with folate deficiency, we etablished mouse embryonic stem cells (mESCs) Sv/129 in folate-deficiency-treated.
2022-09-20 | GSE204869 | GEO
Project description:Folic acid deficiency during pregnancy is believed to be a high-risk factor for neural tube defects (NTDs). Disturbed epigenetic modifications, including miRNA regulation, have been linked to the pathogenesis of NTDs in those with folate deficiency. However, the mechanism by which folic acid-regulated miRNA influences this pathogenesis remains unclear. It is believed that DNA methylation is associated with dysregulated miRNA expression. To clarify this issue, here we measured the methylation changes of 22 miRNAs in 57 human NTD cases to explore whether such changes are involved in miRNA regulation in NTD cases through folate metabolism. In total, eight of the 22 miRNAs tested reduced their methylation modifications in NTD cases, which provide direct evidence of the roles of interactions between DNA methylation and miRNA level in these defects. Among the findings, there was a significant association between folic acid concentration and hsa-let-7 g methylation level in NTD cases. Hypomethylation of hsa-let-7 g increased its own expression level in both NTD cases and cell models, which indicated that hsa-let-7 g methylation directly regulates its own expression. Overexpression of hsa-let-7 g, along with its target genes, disturbed the migration and proliferation of SK-N-SH cells, implying that hsa-let-7 g plays important roles in the prevention of NTDs by folic acid. In summary, our data suggest a relationship between aberrant methylation of hsa-let-7 g and disturbed folate metabolism in NTDs, implying that improvements in nutrition during early pregnancy may prevent such defects, possibly via the donation of methyl groups for miRNAs.
| S-EPMC5706510 | biostudies-literature
Project description:Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 to 200 per 10,000 births with the United States of American NTD incidence at around 3-6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35-50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.
| S-EPMC5650505 | biostudies-literature
Project description:Neural tube closure takes place during early embryogenesis and requires interactions between genetic and environmental factors. Failure of neural tube closure is a common congenital malformation that results in morbidity and mortality. A major clinical achievement has been the use of periconceptional folic acid supplements, which prevents approximately 50-75% of cases of neural tube defects. However, the mechanism underlying the beneficial effects of folic acid is far from clear. Biochemical, genetic and epidemiological observations have led to the development of the methylation hypothesis, which suggests that folic acid prevents neural tube defects by stimulating cellular methylation reactions. Exploring the methylation hypothesis could direct us towards additional strategies to prevent neural tube defects.
| S-EPMC2970514 | biostudies-literature
Project description:BACKGROUND:Neural tube defects (NTDs) are common congenital malformations resulting in failure of the neural tube closure during early embryonic development. Although it is known that maternal folate deficiency increases the risk of NTDs, the mechanism remains elusive. RESULTS:Herein, we report that histone H2A monoubiquitination (H2AK119ub1) plays a role in neural tube closure. We found that the folate antagonist methotrexate induced H2AK119ub1 in mouse embryonic stem cells. We demonstrated that an increase in H2AK119ub1 downregulated expression of the neural tube closure-related genes Cdx2, Nes, Pax6, and Gata4 in mouse embryonic stem cells under folate deficiency conditions. We also determined that the E3 ligase Mdm2 was responsible for the methotrexate-induced increase in H2AK119ub1 and downregulation of neural tube closure-related genes. Surprisingly, we found that Mdm2 is required for MTX-induced H2A ubiquitination and is recruited to the sites of DSB, which is dependent on DNA damage signaling kinase ATM. Furthermore, folic acid supplementation restored H2AK119ub1 binding to neural tube closure-related genes. Downregulation of these genes was also observed in both brain tissue of mouse and human NTD cases, and high levels of H2AK119ub1 were found in the corresponding NTDs samples with their maternal serum folate under low levels. Pearson correlation analysis showed a significant negative correlation between expression of the neural precursor genes and H2AK119ub1. CONCLUSION:Our results indicate that folate deficiency contributes to the onset of NTDs by altering H2AK119ub1 and subsequently affecting expression of neural tube closure-related genes. This may be a potential risk factor for NTDs in response to folate deficiency.
| S-EPMC6852770 | biostudies-literature
Project description:BackgroundFolic acid prevents neural tube closure defects (NTDs), but the causal metabolic pathways have not been established. Serine hydroxymethyltransferase 1 (SHMT1) is an essential scaffold protein in folate-dependent de novo thymidylate synthesis in the nucleus. SHMT1-deficient mice provide a model to investigate folic acid-responsive NTDs wherein disruption of de novo thymidylate synthesis impairs neural tube closure.ObjectiveWe examined the effects of maternal supplementation with the pyrimidine nucleosides uridine, thymidine, or deoxyuridine with and without folate deficiency on NTD incidence in the Shmt1 mouse model.DesignShmt1(+/+) and Shmt1(-/-) female mice fed folate-replete or folate-deficient diets and supplemented with uridine, thymidine, or deoxyuridine were bred, and litters (n = 10-23 per group) were examined for the presence of NTDs. Biomarkers of impaired folate status and metabolism were measured, including plasma nucleosides, hepatic uracil content, maternal plasma folate concentrations, and incorporation of nucleoside precursors into DNA.ResultsShmt1(+/-) and Shmt1(-/-) embryos from dams fed the folate-deficient diet were susceptible to NTDs. No NTDs were observed in litters from dams fed the folate-deficient diet supplemented with deoxyuridine. Surprisingly, uridine supplementation increased NTD incidence, independent of embryo genotype and dietary folic acid. These dietary nucleosides did not affect maternal hepatic uracil accumulation in DNA but did affect plasma folate concentrations.ConclusionsMaternal deoxyuridine supplementation prevented NTDs in dams fed the folate-deficient diet, whereas maternal uridine supplementation increased NTD incidence, independent of folate and embryo genotype. These findings provide new insights into the metabolic impairments and mechanisms of folate-responsive NTDs resulting from decreased Shmt1 expression.
| S-EPMC4381776 | biostudies-literature
Project description:DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5-formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs.
| S-EPMC4379001 | biostudies-literature