Dynamic Change of Shanks Gene mRNA Expression and DNA Methylation in Epileptic Rat Model and Human Patients

Synaptic protein shanks (SH3 and multiple ankyrin repeat domains protein, Shank) have emerged as an important mediator of synaptic remodeling. Synaptic remodeling is a common pathogenic process in various neurological disorders including epilepsy. However, the expression and function of shanks gene in epileptogenesis has not been investigated to date. Herein, we investigated the expression of shanks (shank1/2/3) mRNA expression in both epileptic rats and epilepsy patients. Furthermore, methyl target sequencing was applied to explore the relationship between shank mRNA expression and DNA methylation in both rats and human patients. In general rat model, shank1/2/3 mRNA was downregulated at acute stage, upregulated at latent stage, and returned to the basal level at chronic stage. Ten CpG sites of shank1 was found differentially methylated, out of which 6 were hypermethylated. Seventeen CpG sites of shank3 were differentially methylated, out of which 8 were hypermethylated. In human epilepsy patients, decreased shank2 mRNA was detected from the brain tissue, with DNA hypermethylation dominant from both brain (18 out of 30) and blood tissue (58 out of 80), indicating the regulation role of DNA methylation on shank2 expression. In conclusion, our finding suggests the participation of the shanks gene in the pathophysiology of seizure, out of which 2 shank3 CpG sites (Chr7: 130473419, and Chr7: 130473405) may play an important role in shank3 expression at both the acute and latent stages in the SE rat model.