Altered GNAS imprinting due to folic acid deficiency contributes to poor embryo development and may lead to neural tube defects

// Li Wang 1 , Shaoyan Chang 1 , Zhen Wang 1 , Shan Wang 1 , Junsheng Huo 2 , Gangqiang Ding 2 , Rui Li 1 , Chi Liu 1 , Shaofang Shangguan 1 , Xiaolin Lu 1 , Ting Zhang 1 , Zhiyong Qiu 1, * and Jianxin Wu 1 1 Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, P.R. China 2 National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing, P.R. China * Senior author for project Correspondence to: Jianxin Wu, email: jianxinwu_2000@163.com Keywords: GNAS imprinting gene; folic acid; embryo development; neural tube defects; methylation Received: September 01, 2017      Accepted: October 29, 2017      Published: November 28, 2017 ABSTRACT Disturbed epigenetic modifications have been linked to the pathogenesis of Neural Tube Defects (NTDs) in those with folate deficiency during pregnancy. However, evidence is lacking to delineate the critical region in epigenome regulated by parental folic acid and mechanisms by which folate deficiency affects normal embryogenesis. Our data from clinical samples revealed the presence of aberrant DNA methylation in GNAS imprinting cluster in NTD samples with low folate concentrations. Results from mouse models indicated that the establishment of GNAS imprinting was influenced by both maternal and paternal folate-deficient diets. Such aberrant GNAS imprinting was present prior to the gametogenesis period. Imprinting in Exon1A/GNAS gDMR was abolished in both spermatozoa and oocytes upon treating with a parental folate-deficient diet (3.6% in spermatozoa, 9.8% in oocytes). Interestingly, loss of imprinting in the GNAS gene cluster altered chromatin structure to an overwhelmingly open structure (58.48% in the folate-free medium group vs. 39.51% in the folate-normal medium group; P < 0.05), and led to a disturbed expression of genes in this region. Furthermore, an elevated cyclic AMP levels was observed in folate acid deficiency group. Our results imply that GNAS imprinting plays major roles in folic acid metabolism regulation during embryogenesis. Aberrant GNAS imprinting is an attribute to NTDs, providing a new perspective for explaining the molecular mechanisms by which folate supplementation in human pregnancy provides protection from NTDs.