{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:59:57Z","timestamp":1779170397694,"version":"3.51.4"},"posted":{"date-parts":[[2024,2,23]]},"group-title":"Developmental Biology","reference-count":110,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>Tet1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  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 implicated in intracellular endocytic trafficking and developmental signaling. NTDs across\n                  <jats:italic>Tet1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  strains are resistant to FA supplementation. However, both excess and depleted maternal FA diets modify the impact of\n                  <jats:italic>Tet1<\/jats:italic>\n                  loss on offspring DNA methylation primarily at neurodevelopmental loci. FA deficiency reveals susceptibility to NTD and other structural brain defects due to haploinsufficiency of\n                  <jats:italic>Tet1<\/jats:italic>\n                  . In contrast, excess FA in\n                  <jats:italic>Tet1<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  embryos drives promoter DNA hypermethylation and reduced expression of multiple membrane solute transporters, including a FA transporter, accompanied by loss of phospholipid metabolites. Overall, our study unravels interactions between modified maternal FA status,\n                  <jats:italic>Tet1<\/jats:italic>\n                  gene dosage and genetic backgrounds that impact neurotransmitter functions, cellular methylation and individual susceptibilities to congenital malformations, further implicating that epigenetic dysregulation may underlie NTDs resistant to FA supplementation.\n                <\/jats:p>","DOI":"10.1101\/2024.02.21.581196","type":"posted-content","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T11:56:29Z","timestamp":1709034989000},"source":"Crossref","is-referenced-by-count":2,"title":["Epigenetic regulation by TET1 in gene-environmental interactions influencing susceptibility to congenital malformations"],"prefix":"10.64898","author":[{"given":"Bernard K.","family":"van der Veer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lehua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spyridon Champeris","family":"Tsaniras","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wannes","family":"Brangers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5909-3959","authenticated-orcid":false,"given":"Qiuying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Schroiff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"Custers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harm H.M.","family":"Kwak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Khoueiry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Cabrera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven S.","family":"Gross","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard H.","family":"Finnell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunping","family":"Lei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kian Peng","family":"Koh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024071010202477000_2024.02.21.581196v2.1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151586"},{"key":"2024071010202477000_2024.02.21.581196v2.2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.145904"},{"key":"2024071010202477000_2024.02.21.581196v2.3","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1007\/s00018-012-1227-7","article-title":"How to form and close the brain: insight into the mechanism of cranial neural tube closure in mammals","volume":"70","year":"2013","journal-title":"Cell Mol Life Sci"},{"key":"2024071010202477000_2024.02.21.581196v2.4","doi-asserted-by":"crossref","unstructured":"J. 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