Xiaolin Lu
Capital Institute of Pediatrics, China
Title: Sonic hedgehog signaling affected by promoter hypermethylation induces aberrant Gli2 expression in Spina Bifida
Biography
Biography: Xiaolin Lu
Abstract
SHH signaling pathway played an important role in the formation of dorsal ventral neural plate. It has been shown in mice that genes of SHH signaling pathway mutations increased the incidence of NTDs, such as spina bifida and brain anomalies. Moreover, the single nucleotide polymorphisms (SNPs) of several key genes belonging to SHH pathway have been verified to increase the risk of NTDs in our previous studies. 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 the 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 distributed significantly differently between the two groups, although gli2 methylation levels were significantly increased in spina bifida samples, accompanied by aberrant GLI2 expression. Moreover, a significant negative correlation was found between the folate level of brain tissue and the gli2 methylation status (r=−0.41, P=0.014), while 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). We also used 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 less expression along with decreased expression of gli2 in the 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.