DNA methylation aberrations rather than polymorphisms of FZD3 gene increase the risk of spina bifida in a high-risk region for neural tube defects.
DNA methylation aberrations rather than polymorphisms of FZD3 gene increase the risk of spina bifida in a high-risk region for neural tube defects.
复制标题
DNA 甲基化畸变而非 FZD3 基因多态性增加了神经管缺陷高危区域脊柱裂的风险。
DOI：
10.1002/bdra.23285
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Zhang Ting
中科院分区：
文献类型：
--
作者：
Shangguan Shaofang;Wang Li;Chang Shaoyan;Lu Xiaoling;Wang Zhen;Wu Lihua;Wang Jianhua;Wang Xiuwei;Guan Zhen;Bao Yihua;Zhao Huizhi;Zou Jizhen;Niu Bo;Zhang Ting
动物神经管缺陷（NTDs）模型已经表明fzd3基因和平面细胞极性信号通路在趋同扩展中起作用。我们研究了与人类NTDs，特别是脊柱裂相关的offzd3的遗传和表观遗传机制。我们探索了跨越fzd3基因变异在NTDs中的影响，并研究了fzd3启动子异常甲基化对脊柱裂脑组织中基因表达的作用。方法采用MassARRAY系统对165例NTD胎儿和152例对照组的sixfzd3单核苷酸多态性进行基因分型。使用MassARRAY EpiTYPER（转录起始位点- 500至- 2400 bp的17个CpG单位）检测了77例脊柱裂胎儿和74例对照胎儿脑组织中fzd3启动子区域的DNA甲基化畸变。结果6个单核苷酸多态性中，没有一个与脊柱裂有显著相关性，但脊柱裂样本的平均甲基化水平（13.70%）显著高于对照组（10.91%）（p= 0.001）。在特异性位点方面，脊柱裂样本中17个CpG单元中有14个的DNA甲基化水平显著较高，其中大部分包括在R2区域。在HeLa细胞中，FZD3mRNA的表达与fzd3启动子区甲基化呈负相关，尤其是R2区（R = 0.970;p= 0.001）。结论DNA甲基化在脊柱裂的发病风险中起重要作用，可能与脊柱裂的发病风险增加有关。出生缺陷研究（A辑）(3):37 - 44,2015。©2014 Wiley期刊公司
BACKGROUNDAnimal models of neural tube defects (NTDs) have indicated roles for theFzd3gene and the planar cell polarity signaling pathway in convergent extension. We investigated the involvement ofFZD3in genetic and epigenetic mechanisms associated with human NTDs, especially spina bifida. We explored the effects of variants spanning theFZD3gene in NTDs and examined the role of aberrant methylation of theFZD3promoter on gene expression in brain tissue in spina bifida.METHODSSixFZD3single nucleotide polymorphisms were genotyped using a MassARRAY system in tissue from 165 NTD fetuses and 152 controls. DNA methylation aberrations in theFZD3promoter region were detected using a MassARRAY EpiTYPER (17 CpG units from −500 to −2400 bp from the transcription start site) in brain tissue from 77 spina bifida and 74 control fetuses.RESULTSNone of the six single nucleotide polymorphisms evaluated were significantly associated with spina bifida, but the mean methylation level was significantly higher in spina bifida samples (13.70%) compared with control samples (10.91%) (p= 0.001). In terms of specific sites, DNA methylation levels were significantly higher in the spina bifida samples at 14 of the 17 CpG units, which mostly included in R2 region.FZD3mRNA expression was negatively correlated with methylation of theFZD3promoter region, especially the R2 region (R = 0.970;p= 0.001) in HeLa cells.CONCLUSIONThe results of this study suggest that DNA methylation plays an important role inFZD3gene expression regulation and may be associated with an increased risk of spina bifida. Birth Defects Research (Part A) 103:37–44, 2015. © 2014 Wiley Periodicals, Inc.