Epigenetic regulation by TET1 in gene-environmental interactions influencing susceptibility to congenital malformations.

ABSTRACT: The etiology of neural tube defects (NTDs) involves complex gene-environmental interactions. Folic acid (FA) prevents NTDs, but the mechanisms remain poorly understood and at least 30% of human NTDs resist the beneficial effects of FA supplementation. Here, we identify the DNA demethylase TET1 as a nexus of folate-dependent one-carbon metabolism and genetic risk factors post-neural tube closure. We determine that cranial NTDs in Tet1 ^-/- embryos occur at two to three times higher penetrance in genetically heterogeneous than in homogeneous genetic backgrounds, suggesting a strong impact of genetic modifiers on phenotypic expression. Quantitative trait locus mapping identified a strong NTD risk locus in the 129S6 strain, which harbors missense and modifier variants at genes

SUBMITTER: van der Veer BK 

PROVIDER: S-EPMC11257484 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature