The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE276883 | GEO | 2024/11/08
REPOSITORIES: GEO
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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
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 | GSE275393 | GEO
Project description:Neural tube defects (NTDs) are serious birth defects with an estimated worldwide incidence of 1 per 1,000 live births. The multifactorial nature of NTDs in humans has made it difficult to elucidate pathogenesis mechanisms. However, a strong relationship has been established between folate-homocysteine metabolism and NTD risk. Prevention of a substantial proportion of fetal NTDs can be achieved through maternal folic acid (FA) supplementation. However the mechanism by which FA exerts its beneficial effect remains unclear. METHODS: To improve our understanding of the underlying mechanisms of NTD pathogenesis and the ways in which folate exerts its beneficial effect, we analyzed mRNA profiles as well as folate and vitamin B12 levels in five NTD mouse mutants whose response to dietary FA was previously established. RESULTS: Differentially expressed genes representing the effect of each NTD-causing mutation were identified and associated with biologic pathways. Interestingly, the panel of NTD mutants collectively revealed pathways related to two nuclear receptors, retinoid X receptor (RXR) and pregnane X receptor (PXR), suggesting that these pathways may be related to a shared mechanism of NTD development. Moreover, the NTD-causing mutations that were associated with FA responsiveness had expression profiles that were related to folate-homocysteine metabolic pathways. These pathways were not strongly associated with mutants that do not respond to FA supplementation, implying that FA may be beneficial when the NTD mutation affects pathways related to folate-homocysteine metabolism. 5 groups of NTD mutants were studied. From each mutant group Heterozygous (test) and wild-type (control) female pups were used for this study at 6-8 weeks of age. 4 biological replicates were used for each of the test and control groups of each mutant. All mice used for the experiments were fasted 4-5 hours before dissection. A total of 36 samples were analyzed.
2013-09-30 | E-GEOD-51285 | biostudies-arrayexpress
Project description:Neural tube defects (NTDs) are serious birth defects with an estimated worldwide incidence of 1 per 1,000 live births. The multifactorial nature of NTDs in humans has made it difficult to elucidate pathogenesis mechanisms. However, a strong relationship has been established between folate-homocysteine metabolism and NTD risk. Prevention of a substantial proportion of fetal NTDs can be achieved through maternal folic acid (FA) supplementation. However the mechanism by which FA exerts its beneficial effect remains unclear. METHODS: To improve our understanding of the underlying mechanisms of NTD pathogenesis and the ways in which folate exerts its beneficial effect, we analyzed mRNA profiles as well as folate and vitamin B12 levels in five NTD mouse mutants whose response to dietary FA was previously established. RESULTS: Differentially expressed genes representing the effect of each NTD-causing mutation were identified and associated with biologic pathways. Interestingly, the panel of NTD mutants collectively revealed pathways related to two nuclear receptors, retinoid X receptor (RXR) and pregnane X receptor (PXR), suggesting that these pathways may be related to a shared mechanism of NTD development. Moreover, the NTD-causing mutations that were associated with FA responsiveness had expression profiles that were related to folate-homocysteine metabolic pathways. These pathways were not strongly associated with mutants that do not respond to FA supplementation, implying that FA may be beneficial when the NTD mutation affects pathways related to folate-homocysteine metabolism.
2013-09-30 | GSE51285 | GEO
Project description:Background: Although adequate periconceptional folic acid (FA) supplementation has reduced the occurrence of neural tube defects (NTDs)-affected pregnancies, mechanisms underlie FA resistant NTDs are poorly understood, so that NTDs still remain a global public health concern now. It has been proven that high level of Krüppel-like factor 12 (KLF12) has bad effects on heath in most cases, but there is no evidence concerning its roles during development. Methods: We used KLF12-overexpression mice to study the effects of high level of KLF12 on neural tube development. Findings: We showed KLF12-overexpression fetuses died in utero at around 10.5 days post coitus with 100% cranial NTDs. Neither FA or formate benefited normal neural tube closure in mutant fetuses. Further anylasis revealed high level of KLF12 caused NTDs in mice via overactivating Sonic hedgehog (Shh) signaling pathway, leading to upregulation of Ptch1, Gli1, Hhip etc. PF-5274857, an antagonist of Shh signaling pathway could significantly promote dorsolateral hinge point formation and partially rescue the phynotype. Interpretation: The regulatory hierarchy between high level of KLF12 and FA-resistant NTDs might provide new insights for the diagnosis and treatment of unexplained NTDs in the future.
2021-02-04 | GSE166054 | GEO
Project description:The goal of this study was to assess changes in gene expression and DNA methylation in response to embryonic exposures to the plasticizer metabolite, mono-2-ethylhexyl phthalate (MEHP). Because we previously observed increased incidence of neural tube defects (NTDs) in exposed embryos, we also stratified our samples by NTD status to examine changes in expression or methylation that may be associated with NTD progression in response to MEHP.
2024-07-31 | GSE180254 | GEO
Project description:This data series was used for two separate studies. The initial study was aimed to idenify expression changes brought about by the Cecr2Gt45Bic mutation during neural closure. The study included two different strains, BALB/cCrl in which Cecr2GT45Bic shows a neural tube defect phenotype and FVB/N in which Cecr2Gt45Bic does not manifest neural closure defects. The second was to idenify strain specific expression differences present during neural closure of the mouse embryo between BALB/cCrl and FVB/N in order to identify candidate modifiers of the Cecr2Gt45Bic neural tube defect. Relevant abstracts are included below. The initial study ; BACKGROUND: Over 200 mouse genes are associated with neural tube defects (NTDs), including Cecr2, the bromodomain-containing subunit of the CERF chromatin remodeling complex. METHODS: Gene-trap mutation Cecr2Gt45Bic results in 74% exencephaly (equivalent of human anencephaly) on the BALB/c strain. Gene expression altered during cranial neural tube closure by the Cecr2 mutation was identified through microarray analysis of 11M-bM-^@M-^S14 somites stage Cecr2Gt45Bicembryos. RESULTS: Analysis of Affymetrix Mouse 430 2.0 chips detected 60 transcripts up-regulated and 54 transcripts down-regulated in the Cecr2Gt45Bic embryos (fold > 1.5, p < 0.05). The Cecr2 transcript was reduced only M-bM-^HM-<7- to 14-fold from normal levels, suggesting the Cecr2Gt45Bic is a hypomorphic mutation. We therefore generated a novel Cecr2 null allele (Cecr2tm1.1Hemc). Resulting mutants displayed a stronger penetrance of exencephaly than Cecr2Gt45Bic in both BALB/c and FVB/N strains, in addition to midline facial clefts and forebrain encephalocele in the FVB/N strain. The Cecr2 transcript is reduced 260-fold in the Cecr2tm1.1Hemc line. Subsequent qRT-PCR using Cecr2tm1.1Hemc mutant heads confirmed downregulation of transcription factors Alx1/Cart1,Dlx5, Eya1, and Six1. CONCLUSIONS: As both Alx1/Cart1 and Dlx5 mouse mutations result in exencephaly, we hypothesize that changes in expression of these mesenchymal/ectodermal transcription factors may contribute to NTDs associated with Cecr2. Birth Defects Research (Part A), 2010. 010 Wiley-Liss, Inc. The second study: ABSTRACT:Although neural tube defects (NTDs) are common in humans, little is known about their multifactorial genetic causes. While most mouse models involve NTDs caused by a single mutated gene, we have previously described a multigenic system involving susceptibility to NTDs. In mice with a mutation in Cecr2, the cranial NTD exencephaly shows strain specific differences in penetrance, with 74% penetrance in BALB/cCrl and 0% penetrance in FVB/N. Whole genome linkage analysis showed that a region of chromosome 19 was partially responsible for this difference in penetrance. We now reveal by genetic analysis of three subinterval congenic lines that the chromosome 19 region contains more than one modifier gene. Analysis of embryos showed that although a Cecr2 mutation causes wider neural tubes in both strains, FVB/N embryos overcome this abnormality and close. A microarray analysis comparing neurulating female embryos from both strains identified differentially expressed genes within the chromosome 19 region, including Arhgap19, which is expressed at a lower level in BALB/cCrl due to a stop codon specific to that substrain. Modifier genes in this region are of particular interest because it is syntenic to human chromosome 10q25, the site of a human susceptibility locus. (MANUSCRIPT PENDING SUBMISSION) Thieler STAGE 13-14 (11-14 somite) female embryos where disected away from extraembryonic membranes for RNA extraction and hybridization on Affymetrix microarrays. A single embryo was processed per array, with four biological replicates per genotype BALB/cCrl, Cecr2GT45Bic BALB/cCrl, FVB/N, and Cecr2Gt45Bic FVB/N.
2012-02-27 | E-GEOD-30957 | biostudies-arrayexpress
Project description:Purpose: Identify genes and pathways affected in tuft embryos with NTDs Results: Expression of genes associated with neural tube closure and components of non-canonical WNT signaling/PCP pathways were affected Conclusions: TET1 regulates genes associated with neural tube closure
2016-05-04 | GSE75001 | GEO
Project description:Neural tube defects (NTDs) including anencephaly and spina bifida are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or life-long severe complications (spina bifida). Despite hundreds of genetic mouse models having neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals such as antiseizure medications have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette spheroid (SOSRS) brain organoid system, we have developed a high-throughput image analysis pipeline for evaluating SOSRS structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. This expansion was mimicked by GSK3b and HDAC inhibitors; however, RNA sequencing suggests VPA does not inhibit GSK3b at these concentrations. Knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity.
2023-07-19 | GSE232218 | GEO
Project description:Gpr161 and Fuz are Shh signaling molecules, and both null mutations are associated with neural tube defects in mice. As their genetic relationship in Shh signaling during neural tube development is unknown, we generated double homozygous null mutant mice for phenotyping and associated molecular changes. We observed the rescued NTD phenotypes in double homozygous null mutant embryos compared to those in single Gpr161 null mutant embryos. However, the range of rescued phenotypes is distinct between anterior and posterior NTDs. Therefore, we sought to identify the comparison in gene expression between the anterior and posterior regions of each genotype embryos and between each genotype.
2024-09-26 | GSE270328 | GEO