The effect of folic acid deficiency on Mest/Peg1 in neural tube defects

Abstract

Objective

Neural tube defects (NTDs) are one of the most common and serious birth defects in human beings caused by genetic and environmental factors. Folate insufficiency is involved in the occurrence of NTDs and folic acid supplementation can prevent NTDs occurrence, however, the underlying mechanism remains poorly understood.

Methods

We established cell and animal models of folic acid deficiency to detect the methylation modification and expression levels of genes by MassARRAY and real-time PCR, respectively. Results and conclusion: In the present study, we found firstly that in human folic acid-insufficient NTDs, the methylation level of imprinted gene Mest/Peg1 was decreased. By using a folic acid-deficient cell model, we demonstrated that Mest/Peg1 methylation was descended. Meanwhile, the mRNA level of Mest/Peg1 was up-regulated via hypomethylation modification under low folic acid conditions. Consistent with the results in cell models, Mest/Peg1 expression was elevated through hypomethylation regulation in folate-deficient animal models. Furthermore, the up-regulation of Mest/Peg1 inhibited the expression of Lrp6 gene, a crucial component of Wnt pathway. Similar results with Lrp6 down-regulation of fetal brain were verified in animal models under folic acid-deficient condition. Taken together, our findings indicated folic acid increased the expression of Mest/Peg1 via hypomethylation modification, and then inhibited Lrp6 expression, which may ultimately impact on the development of nervous system through the inactivation of Wnt pathway.

Keywords:

• Mest/Peg1
• Folic acid
• Neural tube defects (NTDs
• )
• Lrp6
• Methylation modification

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical standards

The experimental procedures and the animal use and care protocols were approved by the Committee on the Ethical Use of Animals of Capital Institute of Pediatrics.

Additional information

Funding

This work was supported by the National Natural Science Fund of China (grant nos. 81670802, 81741023), National Key Research and Development Program (grant no. 2016YFC1000502), CAMS Initiative for Innovative Medicine (grant no. CAMS-I2M -1-008), Medicine Research, BJ (2016-04).