Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida
Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida
复制标题
受启动子高甲基化影响的 Sonic Hedgehog 信号传导可诱导脊柱裂中 Gli2 的异常表达。
DOI：
10.1007/s12035-015-9447-0
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发表时间：
2016-10-01
影响因子：
5.1
通讯作者：
Zhang, Ting
中科院分区：
文献类型：
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作者：
Lu, Xiao-Lin;Wang, Li;Zhang, Ting
GLI 2是音刺猬（Shh）信号通路的关键介质，并在脊椎动物胚胎发育过程中的神经管发育中发挥重要作用;然而，在人类叶酸相关的神经管缺陷中，GLI 2的作用仍不清楚。在本研究中，我们比较了脊柱裂患者和对照组之间gli 2基因甲基化状态和多态性，以探讨脊柱裂患者叶酸缺乏的潜在机制。两组之间没有发现单核苷酸多态性有显著差异，尽管在脊柱裂样本中gli 2甲基化水平显著增加，伴有异常GLI 2表达。此外，脑组织中叶酸水平与gil 2甲基化状态呈显著负相关（r =-0.41，P = 0.014），gil 2高甲基化增加脊柱裂的风险，比值比为12.45（95%置信区间：2.71-57.22，P = 0.001）。此外，我们建立了一个细胞模型来说明gli 2表达的影响和甲基化影响的染色质可及性。在5-氮杂处理的细胞中检测到gli 2和gli 1 mRNA的高表达，而gli 2超甲基化导致染色质不可及，并且与含有转录因子的核蛋白的结合减少。对该通路更有意义的是，发现在我们的细胞模型中，通路的效应基因gli 1的表达水平降低，同时沿着gli 2的表达降低。gli 2基因异常高甲基化导致其在脊柱裂组织中低表达，其表达受染色质状态改变和转录因子结合能力的影响。
GLI2 is a key mediator of the sonic hedgehog (Shh) signaling pathway and plays an important role in neural tube development during vertebrate embryogenesis; however, the role of gli2 in human folate-related neural tube defects remains unclear. In this study, we compared methylation status and polymorphisms of gli2 between spina bifida patients and a control group to explore the underlying mechanisms related to folate deficiency in spina bifida. No single nucleotide polymorphism was found to be significantly different between the two groups, although gli2 methylation levels were significantly increased in spina bifida samples, accompanied by aberrant GLI2 expression. Moreover, a prominent negative correlation was found between the folate level in brain tissue and the gli2 methylation status (r = -0.41, P = 0.014), and gli2 hypermethylation increased the risk of spina bifida with an odds ratio of 12.45 (95 % confidence interval: 2.71-57.22, P = 0.001). In addition, we established a cell model to illustrate the effect of gli2 expression and the accessibility of chromatin affected by methylation. High gli2 and gli1 mRNA expression was detected in 5-Aza-treated cells, while gli2 hypermethylation resulted in chromatin inaccessibility and a reduced association with nuclear proteins containing transcriptional factors. More meaningful to the pathway, the effect gene of the Shh pathway, gli1, was found to have a reduced level of expression along with a decreased expression of gli2 in our cell model. Aberrant high methylation resulted in the low expression of gli2 in spina bifida, which was affected by the change in chromatin status and the capacity of transcription factor binding.