Effect of epigenetic activating of Dlk1-Dio3 imprinted cluster on miR-370 expression due to folate deficiency during nerve development
Effect of epigenetic activating of Dlk1-Dio3 imprinted cluster on miR-370 expression due to folate deficiency during nerve development
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DOI：
10.1016/j.jnutbio.2023.109297
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发表时间：
2023-03-26
影响因子：
5.6
通讯作者：
Wang，Li
中科院分区：
文献类型：
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作者：
Chang，Shaoyan;Min，Jie;Wang，Li
适当的Dlk 1-Dio 3印迹在胚胎发生中起着关键作用，叶酸缺乏可能通过表观遗传调节影响该位点的印迹。然而，叶酸是否以及如何直接影响Dlk 1-Dio 3的印迹状态，从而影响神经发育仍不清楚。在这里，我们发现降低IG-DMR（基因间差异甲基化区域）甲基化在叶酸缺乏的脑膨出在人类，这表明异常Dlk 1-Dio 3印迹状态与叶酸缺乏引起的神经管缺陷（NTDs）。叶酸缺乏的胚胎干细胞也得到了类似的结果。通过miRNA芯片分析，叶酸缺乏导致多种miRNA的变化，包括位于Dlk 1-Dio 3位点的15种miRNA的上调。实时荧光定量PCR证实其中7种miRNAs表达上调，尤其是miR-370。与正常胚胎发育（miR-370在E9.5时表达最高）相反，叶酸缺乏的E13.5胚胎中miRNA-370的异常高和持续表达可能导致NTD。此外，我们发现DNMT 3A（de novo DNA methyltransferases 3A）是miR-370在神经细胞中的直接靶基因，并且DNMT 3A参与了miR-370抑制细胞迁移的作用。最后，在叶酸缺乏小鼠模型中，在胎儿脑组织中发现Dlk 1-Dio 3表观遗传激活，伴随沿着miR-370的上调和DNMT 3A的下调。总的来说，我们的研究结果表明，叶酸在神经发生过程中Dlk 1-Dio 3印迹的表观遗传调控中起着关键作用，揭示了叶酸缺乏时Dlk 1-Dio 3位点miRNA激活的优雅机制。
Proper Dlk1-Dio3 imprinting plays a critical role in embryogenesis, and folic acid deficiency may affect the imprinting of this locus through epigenetic regulation. However, whether and how folic acid directly impacts the imprinting status of Dlk1-Dio3 to affect neural development remain unclear. Here, we found decreased IG-DMR (intergenic -differentially methylated regions) methylation in the folate-deficient encephalocele in humans, suggesting that abnormal Dlk1-Dio3 imprinting status is related to neural tube defects (NTDs) caused by folate deficiency. Similar results were obtained with folate-deficient embryonic stem cells. By miRNA chip analysis, folic acid deficiency led to changes in multiple miRNAs, including the upregulation of 15 miRNAs located in the Dlk1-Dio3 locus. Real-time PCR confirmed that seven of these miRNAs were upregulated, especially miR-370. In contrast to normal embryonic development, in which expression of miR-370 is highest at E9.5, the abnormally high and sustained expression of miRNA-370 in folate-deficient E13.5 embryos may contribute to NTDs. In addition, we found thatDNMT3A(de novo DNA methyltransferases 3A) is a direct target gene of miR-370 in neural cells, andDNMT3Aparticipates in the role of miR-370 in inhibiting cell migration. Finally, in the folate-deficient mouse model, Dlk1-Dio3 epigenetic activation was found in fetal brain tissue, along with the upregulation of miR-370 and the downregulation ofDNMT3A. Collectively, our findings demonstrate a pivotal role of folate in the epigenetic regulation of Dlk1-Dio3 imprinting during neurogenesis, revealing an elegant mechanism for the activation of Dlk1-Dio3 locus miRNAs in folic acid deficiency.