کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1946363 | 1054220 | 2015 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition Alteration of Scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition](/preview/png/1946363.png)
• Scn3a expression is downregulated and − 39C site is methylated during development.
• The methylation of the − 39C site in the Scn3a promoter reduces gene expression.
• MBD2 prefers to bind to the promoter element containing the methylated − 39C site.
• MBD2 knockdown upregulates Scn3a mRNA expression by methylating the − 39C site.
• MBD2 and − 39C demethylation are involved in Scn3a upregulation in seizure mice.
Increased expression of sodium channel SCN3A, an embryonic-expressed gene, has been identified in epileptic tissues, which is believed to contribute to the development of epilepsy. However, the regulatory mechanism of SCN3A expression under epileptic condition is still unknown. Here we showed a high level of Scn3a mRNA expression in mouse embryonic hippocampus with gradually decreasing to a low level during the postnatal development and a methylation of a specific CpG site (− 39C) in the Scn3a promoter was increased in hippocampus during postnatal development, corresponding to the downregulation of Scn3a expression. Furthermore, in vitro methylation and − 39C > T mutation of the Scn3a promoter decreased the reporter gene expression, suggesting an important role of the − 39C site in regulating gene expression. We then demonstrated that the sequence containing − 39C was a MBD2-binding motif and the CpG methylation of the promoter region increased the capability of MBD2's binding to the motif. Knockdown of MBD2 in mouse N1E-115 cells led to the − 39C methylation and the downregulation of Scn3a transcription by decreasing the Scn3a promoter activity. In the hippocampus of seizure mice, the expressions of Scn3a and Mbd2 were upregulated after 10-day KA treatment. At the same time point, the − 39C site was demethylated and the capability of MBD2's binding to the Scn3a promoter motif was decreased. Taken together, these findings suggest that CpG methylation and MBD2 are involved in altering Scn3a expression during postnatal development and seizure condition.
Journal: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms - Volume 1849, Issue 1, January 2015, Pages 1–9