The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development
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ABSTRACT:
PROVIDER: PRJNA1150593 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30331700.fastq.gz | Fastqsanger.gz | |||
| SRR30331701.fastq.gz | Fastqsanger.gz | |||
| SRR30331702.fastq.gz | Fastqsanger.gz | |||
| SRR30331703.fastq.gz | Fastqsanger.gz | |||
| SRR30331704.fastq.gz | Fastqsanger.gz |
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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: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
Project description:The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development
| PRJNA1159335 | ENA
Project description:The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development
| PRJNA1150599 | ENA
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.
| S-SCDT-10_1038-S44319-024-00316-1 | biostudies-other
Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. Digital restriction enzyme analysis of methylation (DREAM) was performed to determine the DNA methylation profiles of HEK293T cells overexpressing mTET1-CD, TET1-CD, mTET1-FL, or TET1-FL. In this approach, genomic DNA is sequentially cut at CCCGGG sites with the methylation sensitive enzyme SmaI (blunt ends) and its methylation-tolerant neoschizomer XmaI (5M-bM-^@M-^YCCGG overhangs), creating different end sequences that represent methylation status of the CCCGGG sites. These end sequences are analyzed by next generation sequencing, and thereafter the methylation status at individual CCCGGG sites across the genome can be determined.
2014-06-04 | E-GEOD-44038 | biostudies-arrayexpress
Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. hMeDIP-seq analysis of genomic 5-hydroxymethylcytosine in HEK293T cells overexpressing mTET1-CD, TET1-CD, mTET1-FL, or TET1-FL
2014-06-04 | E-GEOD-44036 | biostudies-arrayexpress
Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. Genome-wdie profiling of gene expression in HEK293T cells following overexpression of wild type or catalytically mutant TET1-FL or TET1-CD
2014-06-04 | E-GEOD-49833 | biostudies-arrayexpress
Project description:We report that full length TET1 (TET1-FL) overexpression fails to induce global DNA demethylation in HEK293T cells. The preferential binding of TET1-FL to hypomethylated CpG islands (CGIs) through its CXXC domain leads to its inhibited 5-hydroxymethylcytosine (5hmC) production as methylation level increases. TET1-FL-induced 5hmC accumulates at CGI edges, while TET1 knockdown induces methylation spreading from methylated edges into hypomethylated CGIs. However, TET1 can regulate gene transcription independent of its dioxygenase catalytic function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically maintains the DNA hypomethylation state of CGIs in adult cells. HEK293T cells were transfected with wild type or catalytically mutant TET1 expression plasmids (TET1-CD, mTET1-CD, TET1-FL and mTET1-FL), or subjected to shRNA-mediated TET1 knockdown. Total RNA samples were extracted and assayed on Affymetrix microarrays
2014-06-04 | E-GEOD-50016 | biostudies-arrayexpress