Low Maternal Dietary Intake of Choline Regulates Toll-Like Receptor 4 Expression Via Histone H3K27me3 in Fetal Mouse Neural Progenitor Cells
Low Maternal Dietary Intake of Choline Regulates Toll-Like Receptor 4 Expression Via Histone H3K27me3 in Fetal Mouse Neural Progenitor Cells
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DOI：
10.1002/mnfr.202000769
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发表时间：
2020-12-13
影响因子：
5.2
通讯作者：
Wang, Yanyan
中科院分区：
文献类型：
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作者：
Guan, Xingying;Chen, Xuedan;Wang, Yanyan
胆碱是一种必需的营养素，也是甲基的主要饮食来源，对大脑发育至关重要。怀孕期间母亲饮食中的低胆碱（LC）改变了胎儿大脑中的神经发生，并导致认知能力低下。然而，神经祖细胞（NPC）发育期间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。方法和结果定时怀孕的Nestin-CFPnuc转基因小鼠在E11-17期间喂食对照饮食或LC饮食。通过RNA测序鉴定分选的E17 NPC中的基因表达变化。母体LC饮食显著增加Tlr 4转录，导致过早的神经元分化和增强的乙醇诱导的NLRP 3炎性小体激活。在Tlr 4基因启动子区的DNA甲基化没有变化，但是，在LC处理的NPC中观察到H3 K27 me 3降低了70%。EZH 2的抑制降低H3 K27 me 3水平并增加Tlr 4表达。相反，应用无催化活性的Cas9与EZH 2在Tlr 4启动子处增加H3 K27 me 3导致Tlr 4 expression.Conclusion这些数据揭示了母体胆碱可用性对脑发育影响的表观遗传机制，提示可能的神经发育疾病干预。
Scope 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.Methods and results 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.Conclusion These data reveal an epigenetic mechanism for the effect of maternal choline availability on brain development, suggesting a likely intervention for neurodevelopmental diseases.