Impaired methylation modifications of FZD3 alter chromatin accessibility and are involved in congenital hydrocephalus pathogenesis
Impaired methylation modifications of FZD3 alter chromatin accessibility and are involved in congenital hydrocephalus pathogenesis
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DOI：
10.1016/j.brainres.2014.04.010
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发表时间：
2014-06
期刊：
影响因子：
2.9
通讯作者：
Li Wang;S. Shangguan;Shaoyan Chang;Zhen Wang;Xiaolin Lu;Lihua Wu;Rui Li;Y. Bao;Z. Qiu;B. Niu;Ting Zhang
中科院分区：
文献类型：
--
作者：
Li Wang;S. Shangguan;Shaoyan Chang;Zhen Wang;Xiaolin Lu;Lihua Wu;Rui Li;Y. Bao;Z. Qiu;B. Niu;Ting Zhang
先天性脑积水的病因是异质性的，除了遗传因素外，已被证明是由环境因素引起的。然而，到目前为止，没有靶基因的甲基化改变与人类先天性脑积水有关。Frizzled 3（FZD 3）是一个平面细胞极性（PCP）基因，是PCP信号转导所必需的。FZD 3突变小鼠部分恢复Frizzled 3活性导致脑积水。为了分析FZD 3基因表观遗传修饰在先天性脑积水发病机制中的可能作用，采用基质辅助激光解吸电离飞行时间质谱法检测FZD 3基因启动子区DNA甲基化。还测定了基因表达和染色质可及性以评估甲基化改变的作用。我们的研究发现FZD 3基因甲基化水平在先天性脑积水中升高，尤其是在男性（10.57±3.90 vs.7.08 ± 0.94，p =0.001）。FZD 3的高甲基化增加了先天性脑积水的风险，比值比为10.125（p=0.003）。FZD 3的异常甲基化修饰改变了该区域的染色质结构和FZD 3的表达水平。总的来说，FZD 3基因的异常甲基化修饰通过改变染色质结构和干扰基因表达增加了先天性脑积水的风险。
Congenital hydrocephalus is heterogeneous in its etiology, and in addition to a genetic component, has been shown to be caused by environmental factors. Until now, however, no methylation alterations of target genes have been connected with congenital hydrocephalus in humans. Frizzled 3(FZD3) is a planar cell polarity (PCP) gene required for PCP signaling. Partial restoration of frizzled 3 activities inFZD3mutant mice results in hydrocephalus. To analyze the possible roles of epigenetic modifications of theFZD3gene in congenital hydrocephalus pathogenesis, DNA methylation in the promoter region ofFZD3was assayed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Gene expression and chromatin accessibility were also determined to assess the role of methylation alterations. Our study found methylation levels of theFZD3gene were increased in congenital hydrocephalus, especially in males (10.57±3.90 vs. 7.08±0.94,p=0.001). Hypermethylation ofFZD3increased congenital hydrocephalus risk, with an odds ratio of 10.125 (p=0.003). Aberrant methylation modification ofFZD3altered both chromatin structure in this region andFZD3expression levels. Totally, aberrant methylation modification of theFZD3gene increases the risk of congenital hydrocephalus by altering chromatin structure and disturbing gene expression.