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The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development.

ABSTRACT: Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1-/- embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/- offspring and to altered DNA hypermethylation in Tet1-/- embryos, primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene that exhibits increased promoter DNA methylation and thereby mimics FA deficiency. Moreover, FA deficiency reveals that Tet1 haploinsufficiency can contribute to DNA hypermethylation and susceptibility to NTDs. Overall, our study suggests that epigenetic dysregulation may underlie NTD development despite FA supplementation.

SUBMITTER: Lehua Chen

PROVIDER: S-SCDT-10_1038-S44319-024-00316-1 | biostudies-other |

REPOSITORIES: biostudies-other

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The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

Project description:Folic acid (FA) prevents neural tube defects (NTDs), but it remains unclear why many cases of human NTDs still occur despite FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal dietary FA status to regulate embryonic brain development. We determined that cranial NTDs in Tet1-/- embryos display higher penetrance in non-inbred than in inbred genetic backgrounds and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of mild cranial deformities in wild type and Tet1+/- offspring and altered DNA hypermethylation in Tet1-/- embryos primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene which exhibits increased promoter DNA methylation, thus mimicking a pseudo-FA deficiency. FA deficiency reveals an impact of Tet1 haploinsufficiency that contributes to DNA hypermethylation and susceptibility to NTDs. Overall, our study reveals that epigenetic dysregulation may underlie the resistance of NTDs to FA supplementation.

2024-10-24 | GSE275401 | GEO

The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

2024-10-24 | GSE275393 | GEO

The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

Project description:Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1-/- embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/- offspring and to altered DNA hypermethylation in Tet1-/- embryos, primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene that exhibits increased promoter DNA methylation and thereby mimics FA deficiency. Moreover, FA deficiency reveals that Tet1 haploinsufficiency can contribute to DNA hypermethylation and susceptibility to NTDs. Overall, our study suggests that epigenetic dysregulation may underlie NTD development despite FA supplementation.

2024-11-08 | GSE276883 | GEO

The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

Project description:The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

| PRJNA1150599 | ENA

The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

Project description:The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

| PRJNA1150593 | ENA

The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

Project description:The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development

| PRJNA1159335 | ENA

Impact of Zinc Transport Mechanisms on Embryonic and Brain Development.

Project description:The trace element zinc (Zn) binds to over ten percent of proteins in eukaryotic cells. Zn flexible chemistry allows it to regulate the activity of hundreds of enzymes and influence scores of metabolic processes in cells throughout the body. Deficiency of Zn in humans has a profound effect on development and in adults later in life, particularly in the brain, where Zn deficiency is linked to several neurological disorders. In this review, we will summarize the importance of Zn during development through a description of the outcomes of both genetic and early dietary Zn deficiency, focusing on the pathological consequences on the whole body and brain. The epidemiology and the symptomology of Zn deficiency in humans will be described, including the most studied inherited Zn deficiency disease, Acrodermatitis enteropathica. In addition, we will give an overview of the different forms and animal models of Zn deficiency, as well as the 24 Zn transporters, distributed into two families: the ZIPs and the ZnTs, which control the balance of Zn throughout the body. Lastly, we will describe the TRPM7 ion channel, which was recently shown to contribute to intestinal Zn absorption and has its own significant impact on early embryonic development.

| S-EPMC9231024 | biostudies-literature

Maternal folic acid supplementation alters gene expression in the offspring brain

Project description:Studies have indicated that altered maternal micronutrients and vitamins influence the development and susceptibility of newborns to chronic diseases. Among these, folic acid (FA) plays a key role in the synthesis and repair of DNA, along with maintenance of epigenetic DNA methylation. Deficiency of FA has been associated with the pathogenesis of neural tube defects. Since FA can modulate DNA methylation and affect gene expression, we investigated the effect of gestational FA supplementation on the expression of genes in the offspring brain. Our results suggest that a maternal ten-fold increase in FA supplementation alters the expression and dysregulates a number of genes in the offspring brain, including many involved in development. While a number of genes that were dysregulated were common to both male and female pups, there were sex differences in gene expression changes. C57BL/6J female mice were separated into two groups of ten mice and supplemented with a custom diet. One week prior to mating the low-dose group of female mice were fed a custom AIN-93G amino acidM-bM-^@M-^Sbased diet (Research Diet, Inc. New-Brunswick, NJ), with FA at 0.4 mg/kg, while the high-dose group received FA at 4 mg/kg diet. Tissues from the cerebral hemisphere of three independent pups of same gender were pooled together. A total of three microarray gene expression studies have been performed (0.4mg/kg or 4mg/kg both male and female) and the mean was used for comparison.

2013-09-09 | E-GEOD-45607 | biostudies-arrayexpress

Maternal Nutritional Status Modifies Heat-Associated Growth Restriction in Women with Chronic Malnutrition

Project description:Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and z-scores of birth length (LGAZ) and head circumference (HCGAZ). Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins and mTORC1 signalling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation (MNS) before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.

2023-02-08 | GSE220877 | GEO

First-Trimester Maternal Folic Acid Supplementation Modifies the Effects of Risk Factors Exposures on Congenital Heart Disease in Offspring.

Project description:This study aimed to examine effect modification of maternal risk factor exposures and congenital heart disease (CHD) by maternal folic acid supplementation (FAS)/non-FAS. We included 8379 CHD cases and 6918 CHD-free controls from 40 clinical centers in Guangdong Province, Southern China, 2004-2016. Controls were randomly chosen from malformation-free fetuses and infants and frequency matched to the echocardiogram-confirmed cases by enrollment hospital and year of birth. We used multiple regression models to evaluate interactions between FAS/non-FAS and risk factors on CHDs and major CHD categories, adjusted for confounding variables. We detected statistically significant additive and multiplicative interactions between maternal FAS/non-FAS and first-trimester fever, viral infection, and threatened abortion on CHDs. An additive interaction on CHDs was also identified between non-FAS and living in a newly renovated home. We observed a statistically significant dose-response relationship between non-FAS and a greater number of maternal risk factors on CHDs. Non-FAS and maternal risk factors interacted additively on multiple critical CHDs, conotruncal defects, and right ventricular outflow tract obstruction. Maternal risk factor exposures may have differential associations with CHD risk in offspring, according to FAS. These findings may inform the design of targeted interventions to prevent CHDs in highly susceptible population groups.

| S-EPMC8399198 | biostudies-literature

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