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DNA methylation in Folbp1 knockout mice supplemented with folic acid during gestation
Richard H Finnell1, Ofer Spiegelstein, Bogdan Wlodarczyk
1Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston 77030, USA. rfinnell@ibt.tamu.edu
Abstract:
Periconceptional folic acid supplementation has been shown to prevent up to 70% of neural tube and other birth defects in humans; however, the mechanism is still unknown. In this study, we tested whether defective intracellular folate transport, as achieved by inactivation of the murine folate-binding protein 1 (Folbp1), affects global DNA methylation in the liver and brain from gestational day (GD) 15 embryos. Complete Folbp1 inactivation is embryolethal but can be reversed by maternal folinic acid (FA) supplementation, and thus we also tested the effect of FA supplementation on DNA methylation in Folbp1 fetuses. Overall, the extent of global DNA methylation seems to be similar across all genotypes in unsupplemented control Folbp1 mice; however, explicit conclusions regarding Folbp1(-/-) fetuses were not possible because only a single living unsupplemented fetus was viable at GD 15. FA supplementation induced global DNA hypomethylation across all genotypes. FA-induced hypomethylation is most likely due to its ability to inhibit the enzyme glycine hydroxymethyltransferase, thereby inhibiting the homocysteine remethylation cycle necessary to regenerate S-adenosylmethionine, the methyl donor for DNA methyltransferases. Our hypothesis was that due to defective folate transport in Folbp1(-/-) embryos and fetuses, DNA would be hypomethylated, thereby altering the temporal expression of critical genes necessary for normal embryonic development. However, these results suggest that an extended examination of changes in DNA methylation prior to GD 15 is required to unequivocally prove or disprove the hypothesis.
Insights
Defective folate transport in mice did not alter DNA methylation at gestational day 15. However, folinic acid supplementation caused global DNA hypomethylation, suggesting a role in regulating methylation patterns during embryonic development.
Area of Science:
- Developmental Biology
- Epigenetics
- Nutritional Biochemistry
Background:
- Periconceptional folic acid prevents birth defects, but the mechanism is unclear.
- Intracellular folate transport is crucial for embryonic development.
- Folate-binding protein 1 (Folbp1) plays a role in folate transport.
Purpose of the Study:
- To investigate the impact of defective folate transport (Folbp1 inactivation) on global DNA methylation in embryonic liver and brain.
- To determine the effect of folinic acid (FA) supplementation on DNA methylation in Folbp1 mutant embryos.
Main Methods:
- Utilized Folbp1 knockout mouse model.
- Assessed global DNA methylation in embryos at gestational day 15.
- Administered maternal folinic acid supplementation to rescue Folbp1 deficiency.
Main Results:
- Global DNA methylation levels were similar across genotypes in unsupplemented Folbp1 mice at GD 15.
- Folinic acid supplementation induced global DNA hypomethylation in all genotypes.
- FA-induced hypomethylation may involve inhibition of glycine hydroxymethyltransferase and the homocysteine remethylation cycle.
Conclusions:
- Defective folate transport via Folbp1 does not appear to significantly alter global DNA methylation by gestational day 15.
- Folinic acid supplementation leads to DNA hypomethylation, suggesting a regulatory role in epigenetic processes.
- Further investigation into earlier developmental stages is needed to fully understand the hypothesis regarding Folbp1, folate transport, and DNA methylation.