The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-11-22 DOI:10.1038/s44319-024-00316-1

Lehua Chen, Bernard K van der Veer, Qiuying Chen, Spyridon Champeris Tsaniras, Wannes Brangers, Harm H M Kwak, Rita Khoueiry, Yunping Lei, Robert Cabrera, Steven S Gross, Richard H Finnell, Kian Peng Koh

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Abstract

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.

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DNA 去甲基化酶 TET1 可改变母体叶酸状况对胚胎大脑发育的影响。

众所周知，叶酸（FA）可以预防神经管畸形（NTD），但我们不知道为什么许多人类NTD病例仍然对补充叶酸难以奏效。在这里，我们研究了DNA去甲基化酶TET1如何与母体的叶酸状态相互作用来调节小鼠胚胎大脑发育。我们发现，颅脑 NTD 在非近亲繁殖的小鼠胚胎中比近亲繁殖的 Tet1-/- 胚胎具有更高的穿透性，而且不同品系的小鼠胚胎对补充足量脂肪酸都有抵抗力。富含或缺乏脂肪酸的母体饮食与野生型和Tet1+/-后代颅骨畸形发生率增加有关，也与Tet1-/-胚胎DNA超甲基化改变有关，主要是在神经发育位点。Tet1-/- 胚胎中过量的 FA 会导致磷脂代谢物的损失和多种膜溶质载体的表达减少，其中包括一种 FA 转运体基因，该基因的启动子 DNA 甲基化增加，从而模拟 FA 缺乏。此外，FA 缺乏症揭示了 Tet1 单倍体缺乏可导致 DNA 高甲基化和 NTD 易感性。总之，我们的研究表明，尽管补充了 FA，但表观遗传失调可能是 NTD 发生的基础。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.