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

The etiology of neural tube defects (NTDs) involves complex gene-environmental interactions. Folate is the largest modifier of NTD risk, but mechanisms remain unclear. Here, we identify the DNA demethylase TET1 as a nexus of folate metabolism and genetic risk factors post-gastrulation. We observed cranial NTDs in Tet1 null embryos at contrasting penetrance in inbred versus genetically heterogenous strains. Furthermore, we identified a risk locus harboring a hotspot of genes co-regulated by a strain-dependent interaction between TET1 and developmental signaling pathways during neural induction. Adverse maternal dietary folic acid (FA) status interacts with the loss of TET1 to affect offspring DNA methylation primarily at neurogenesis loci. Conversely, excess FA in Tet1 null embryos drives promoter DNA hypermethylation and reduced expression of membrane solute transporters, associated with reduced FA intake and disruption of phospholipid metabolism. Overall, our study unravels interactions between modified maternal FA status, Tet1 gene dosage and genetic backgrounds that impact neurotransmitter functions, response to cell-extrinsic inputs, and individual susceptibility to congenital disorders. ### Competing Interest Statement The authors have declared no competing interest.