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

Li Wang,Zhen Wang,Ting Zhang,Junsheng Huo,Chi Liu,Rui Li,Zhiyong Qiu,Shaofang Shangguan,Xiaolin Lu,Shan Wang,Jianxin Wu,Gangqiang Ding,Shaoyan Chang

doi:10.18632/oncotarget.22731

Li Wang, Zhen Wang + Show 11 more

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https://doi.org/10.18632/oncotarget.22731

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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.

Highlights

There is an emerging concept that early life environment may have widespread consequences on individual’s health later in life, starting from zygote stage, through infancy, to adulthood [1]
There was a significant reduction in methylation level, 34.95 ± 4.79% in Neural Tube Defects (NTDs) vs. 40.53 ± 2.94% in controls (P < 0.05), in the Nespas differentially methylated regions (DMRs), one of the three DMRs located in the GNAS imprinting cluster (Figure 1)
It has been well accepted that folic acid deficiency during pregnancy increases the risk of NTDs, and changes in gene methylation regulation during embryogenesis are believed to be involved in the process

Summary

Introduction

There is an emerging concept that early life environment may have widespread consequences on individual’s health later in life, starting from zygote stage, through infancy, to adulthood [1]. Folic acid deficiency has long been recognized as an important contributor to developmental anomalies [4, 7,8,9,10], and has been correlated with increased risk of intrauterine growth restriction (IUGR) and neural tube defects (NTDs), as well as cardiac and limb abnormalities. There is growing evidence that paternal folic acid levels can affect the epigenetic status of the genome [15,16,17]. The effects of folate deficiency on embryo development are extensive, profound, and pleiotropic, evidence is lacking to delineate the critical region in epigenome regulated by parental folic acid and mechanisms by which folate deficiency affects normal embryogenesis

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