Department of Medical Genetics, College of Basic Medical Science, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Undergraduate Student Brigade, College of Basic Medical Science, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
Mol Nutr Food Res. 2021 Jan;65(2):e2000769. doi: 10.1002/mnfr.202000769. Epub 2020 Dec 13.
Choline is an essential nutrient and a primary dietary source of methyl groups that are vital for brain development. Low choline (LC) in the maternal diet during pregnancy alters neurogenesis in the fetal brain and leads to low cognitive performance. However, the key signaling pathways that are sensitive to maternal choline supply during neural progenitor cell (NPC) development and the epigenetic mechanisms by which choline availability regulates gene expression are unclear.
Timed-pregnant Nestin-CFPnuc transgenic mice are fed either a control diet or LC diet during E11-17. Gene expression changes in sorted E17 NPCs are identified by RNA sequencing. A maternal LC diet significantly increases Tlr4 transcription, causing premature neuronal differentiation and enhanced ethanol-induced NLRP3 inflammasome activation. No changes in DNA methylation at the Tlr4 gene promoter region are detected; however, a 70% decrease in H3K27me3 is observed in the LC-treated NPCs. Inhibition of EZH2 decreases H3K27me3 levels and increases Tlr4 expression. Conversely, the application of catalytically inactive Cas9 with EZH2 to increase H3K27me3 at the Tlr4 promoter causes reduced Tlr4 expression.
These data reveal an epigenetic mechanism for the effect of maternal choline availability on brain development, suggesting a likely intervention for neurodevelopmental diseases.
胆碱是一种必需营养素，也是甲基的主要膳食来源，对大脑发育至关重要。妊娠期间母体饮食中胆碱含量低会改变胎儿大脑中的神经发生，导致认知能力下降。然而，在神经祖细胞（NPC）发育过程中对母体胆碱供应敏感的关键信号通路以及胆碱可用性调节基因表达的表观遗传机制尚不清楚。
在 E11-17 期间，用对照饮食或 LC 饮食喂养具有时间性妊娠的巢蛋白-CFPnuc 转基因小鼠。通过 RNA 测序鉴定分选的 E17 NPC 中的基因表达变化。母体 LC 饮食显着增加了 Tlr4 转录，导致过早的神经元分化和增强的乙醇诱导的 NLRP3 炎症小体激活。在 Tlr4 基因启动子区域未检测到 DNA 甲基化的变化；然而，LC 处理的 NPC 中观察到 H3K27me3 减少了 70%。抑制 EZH2 降低了 H3K27me3 水平并增加了 Tlr4 表达。相反，应用具有 EZH2 的无催化活性 Cas9 增加 Tlr4 启动子处的 H3K27me3 会导致 Tlr4 表达减少。
这些数据揭示了母体胆碱可用性对大脑发育影响的表观遗传机制，表明这可能是神经发育性疾病的一种干预措施。
