叶酸通过DNA甲基化途径对脑发育表观遗传学作用机制的研究

项目名称： 叶酸通过DNA甲基化途径对脑发育表观遗传学作用机制的研究

项目编号： No.81472967

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 黄国伟

作者单位： 天津医科大学

项目金额： 90万元

中文摘要： 本研究通过动物生殖实验、体外神经干细胞（NSCs）培养及人群队列研究三个层次，脑发育测量、蛋氨酸循环代谢产物、DNA甲基化基因三条途径，探讨叶酸-DNA甲基化-脑发育三者之间的关系。采用大鼠生殖实验，分为孕期叶酸缺乏、短期服用和全程服用叶酸组，每组大鼠产生的同窝子代新生鼠分为三部分：子代新生鼠脑组织；子代新生鼠海马NSCs体外培养；子代新生鼠将继续饲养至3月龄，然后进行检测。人群研究将孕产妇和婴幼儿分为孕前与孕期全程补充叶酸组、怀孕前后短期补充叶酸组以及孕前与孕期均未补充叶酸组，开展为期3年队列研究。检测大鼠子代大脑发育、学习记忆、NSCs增殖分化及婴幼儿神经发育。 检测大鼠子代大脑组织、NSCs、血液及孕妇脐带血中叶酸、蛋氨酸循环产物、5-甲基胞嘧啶、甲基转移酶活性及其基因表达；检测全基因组甲基化状态，找出差异基因，并进行验证。提出叶酸通过DNA甲基化途径对脑发育表观遗传学的作用机制。

中文关键词： 叶酸；脑发育；DNA甲基化；表观遗传学

英文摘要： The aim of this study is to explore the epigenetic effects of folic acid on brain development by DNA methylation. The relationship between folic acid, DNA methylation and brain development will be studied by the three experimental levels and three approach experiments. The three experimental levels are animal reproductive study, neural stem cells (NSCs) in vitro, and population cohort study. The brain development, methionine circulating metabolites and DNA methylation will be detected. Pregnant rats were randomly assigned to 3 groups: folic acid deficient, folic acid supplement for short period, and folic acid supplement for whole period of gestation and before pregnancy. And then pups were randomly assigned to 3 parts: one part pups were killed to get brain tissue, one part pups used to culture hippocampal NSCs in vitro, the last part pups feed till three month. Cohort study follows up women and their infants for three years. The women and their infants will be divided to three groups according to the situation of folic acid supplement during pregnancy: supplement folic acid during whole gestation and before pregnancy, supplement folic acid only a short time, and never supplement folic acid. Brain development, learning and memory abilities of rat offspring and infants will be examined. The levels of folate, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, 5-methylcytosine, DNA methyltransferase activity and genes experession of rat brain tissue and blood and in the umbilical cord blood of women, the proliferation and differentiation of NSCs will be detected. The levels of DNA methylation will be assessed by MeDIP-seq, and differentially methylated regions will be found. The study will elucidate the underlying mechanism of the effects of folic acid deficiency and the different way of folic acid supplement on brain development, and demonstrate the relationship of folate, DNA methylation and brain development. The molecular mechanisms of the epigenetic effects of folic acid on brain development by DNA methylation will be provided. A scientific guideline for folic acid supplement in women will be suggested.

英文关键词： folic acid;brain development;DNA methylation;epigenetics