Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes
Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes
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DOI：
10.1080/15592294.2015.1117889
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发表时间：
2015-12-02
期刊：
影响因子：
3.7
通讯作者：
Wiemels, Joseph L.
中科院分区：
文献类型：
--
作者：
Gonseth, Semira;Roy, Ritu;Wiemels, Joseph L.
早期胚胎发育过程中叶酸缺乏是神经管缺陷的危险因素，并可能通过未知机制导致儿童白血病。我们采用全基因组且不可知的方法测试了受孕前 12 个月内摄入叶酸是否会诱导健康新生儿出生时 DNA 甲基化修饰。我们假设参与神经管发育和/或癌症易感性的基因中的 DNA 甲基化会受到叶酸暴露的影响。我们通过对 343 名健康新生儿的母亲进行食物频率调查问卷，回顾性评估了受孕时叶酸的暴露情况。我们测量了新生儿血斑的全基因组 DNA 甲基化。我们实施了一种基于引导重采样的方法来减少假阳性结果。叶酸与整个基因组的 DNA 甲基化呈负相关。冈比亚的一项独立研究中复制的最重要的叶酸相关基因包括 TFAP2A（一种对神经嵴发育至关重要的基因）、STX11（一种与急性髓系白血病有关的基因）和 CYS1（一种囊性肾病的候选基因）。围孕期叶酸摄入量减少与甲基化增加相关，进而降低这 3 个基因座的基因表达。通过基因集富集分析，由相关 CpG 位点定义的顶级叶酸敏感基因富含多种转录因子，包括那些与癌症发展有关的基因（例如 MYC 相关锌指蛋白）。估计围孕期叶酸摄入量对新生儿 DNA 甲基化水平的影响为了解这种维生素在神经管缺陷和儿童癌症发展中的作用提供了潜在的机制见解。
Folate deficiency during early embryonic development constitutes a risk factor for neural tube defects and potentially for childhood leukemia via unknown mechanisms. We tested whether folate consumption during the 12 months prior to conception induced DNA methylation modifications at birth in healthy neonates with a genome-wide and agnostic approach. We hypothesized that DNA methylation in genes involved in neural tube development and/or cancer susceptibility would be affected by folate exposure. We retrospectively assessed folate exposure at the time of conception by food-frequency questionnaires administered to the mothers of 343 healthy newborns. We measured genome-wide DNA methylation from neonatal blood spots. We implemented a method based on bootstrap resampling to decrease false-positive findings. Folate was inversely associated with DNA methylation throughout the genome. Among the top folate-associated genes that were replicated in an independent Gambian study were TFAP2A, a gene critical for neural crest development, STX11, a gene implicated in acute myeloid leukemia, and CYS1, a candidate gene for cystic kidney disease. Reduced periconceptional folate intake was associated with increased methylation and, in turn, decreased gene expression at these 3 loci. The top folate-sensitive genes defined by their associated CpG sites were enriched for numerous transcription factors by Gene Set Enrichment Analysis, including those implicated in cancer development (e.g., MYC-associated zinc finger protein). The influence of estimated periconceptional folate intake on neonatal DNA methylation levels provides potential mechanistic insights into the role of this vitamin in the development of neural tube defects and childhood cancers.