Yu Min, Li Wen, Luo Suhui, Zhang Yan, Liu Huan, Gao Yuxia, Wang Xuan, Wilson John X, Huang Guowei
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
School of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
J Nutr Biochem. 2014 Apr;25(4):496-502. doi: 10.1016/j.jnutbio.2013.12.010. Epub 2014 Jan 30.
Proliferation of neural stem cells (NSCs) is required for development and repair in the nervous system. NSC amplification in vitro is a necessary step towards using NSC transplantation therapy to treat neurodegenerative diseases. Folic acid (FA) has been shown to act through DNA methyltransferase to stimulate NSC proliferation. To elucidate the underlying mechanism, the effect of FA on the methylation profiles in neonatal rat NSCs was assessed by methylated DNA immunoprecipitation (MeDIP) and methylated DNA immunoprecipitation-DNA microarray (MeDIP-Chip). Differentially methylated regions (DMRs) were determined by quantitative differentially methylated regions analysis, and genes carrying at least three DMRs were selected for pathway analysis. Gene network analysis revealed links with steroid biosynthesis, fatty acid elongation and the PI3K/Akt/CREB, neuroactive ligand-receptor interaction, Jak-STAT and MAPK signaling pathways. Moreover, Akt3 acted as a hub in the network, in which 14 differentially methylated genes converged to the PI3K/Akt/CREB signaling pathway. These findings indicate that FA stimulates NSC proliferation by modifying DNA methylation levels in the PI3K/Akt/CREB pathway.
神经干细胞（NSCs）的增殖是神经系统发育和修复所必需的。NSCs在体外扩增是利用NSC移植疗法治疗神经退行性疾病的必要步骤。叶酸（FA）已被证明可通过DNA甲基转移酶来刺激NSCs增殖。为阐明其潜在机制，通过甲基化DNA免疫沉淀（MeDIP）和甲基化DNA免疫沉淀-芯片（MeDIP-Chip）评估了FA对新生大鼠NSCs甲基化谱的影响。通过定量差异甲基化区域分析确定差异甲基化区域（DMRs），并选择携带至少三个DMRs的基因进行通路分析。基因网络分析揭示了与类固醇生物合成、脂肪酸延长以及PI3K/Akt/CREB、神经活性配体-受体相互作用、Jak-STAT和MAPK信号通路的联系。此外，Akt3在该网络中起枢纽作用，其中14个差异甲基化基因汇聚到PI3K/Akt/CREB信号通路。这些发现表明，FA通过改变PI3K/Akt/CREB通路中的DNA甲基化水平来刺激NSCs增殖。
