叶酸代谢紊乱致神经管畸形(NTDs)发生机制不清楚。rRNA转录-细胞命运决定因子-发育信号通路这一整合路径影响器官形成细胞分化走向。胚胎早期细胞命运决定因子在叶酸代谢变化下是否影响细胞分化走向而影响神经管闭合并不清楚。我们已证实低叶酸NTDs标本上游结合因子（UBF）表达增加同时rRNA基因转录改变，现拟通过叶酸缺乏细胞及动物模型明确叶酸对UBF协同细胞命运决定因子介导rRNA基因转录调控机制及神经干细胞分化去向；采用CHIP-seq、RNA-seq、Co-IP探讨以上分子协同作用对神经外胚层分化及神经管闭合关键通路活性影响；采用DNase-seq探讨叶酸增补对上述整合路径的影响及细胞分化走向的干预机制；结合Nanostring验证NTDs标本中UBF协同细胞命运决定因子调控核糖体基因转录。本项目拟从叶酸影响rRNA转录-细胞命运决定因子-神经管闭合通路路径探讨NTDs病因，促进生殖健康

The mechanism of folic acid metabolic disorder causing neural tube defects (NTDs) is not clear. “rRNA gene transcription - cell fate determination factors - developmental signals” integration pathway affects cell differentiation in organs forming. It is not known whether cell fate determination factors affect the differentiation of cells by folate metabolic environment in early embryo development. In samples from NTDs with low folate level, aberrant UBF level was observed along with up-regulation of rRNA gene transcription in our previous studies. To understand the effects of these synergistic molecules on the key neural tube closure pathways and the differentiation of neuroectoderm, we will use the cell model and animal model in folate deficiency to investigate the mechanism of rRNA gene transcriptional regulation and the differentiation of neural stem cells with the technique of CHIP-seq, RNA-seq and Co-IP.The effects of folic acid supplementation on the above-mentioned integration pathway and the intervention mechanism of cell differentiation will be revealed by DNase-seq. Furthermore, the validation of the function of rRNA gene transcription mediated by UBF interaction with cell fate determination factors will be made in human NTDs samples combined with Nanostring technology. This project attempts to analyse NTDs etiology from the rRNA transcription perspective to improve reproductive health.