Nutri-epigenomic Studies Related to Neural Tube Defects: Does Folate Affect Neural Tube Closure Via Changes in DNA Methylation?

Abstract

Neural tube defects (NTDs), affecting 1-2 per 1000 pregnancies, are severe congenital malformations that arise from the failure of neurulation during early embryonic development. The methylation hypothesis suggests that folate prevents NTDs by stimulating cellular methylation reactions. Folate is central to the one-carbon metabolism that produces pyrimidines and purines for DNA synthesis and for the generation of the methyldonor S-adenosyl-methionine. This review focuses on the relation between the folate-mediated one-carbon metabolism, DNA methylation and NTDs. Studies will be discussed that investigated global or locus-specific DNA methylation differences in patients with NTDs. Folate deficiency may increase NTD risk by decreasing DNA methylation, but to date, human studies vary widely in study design in terms of analyzing different clinical subtypes of NTDs, using different methylation quantification assays and using DNA isolated from diverse types of tissues. Some studies have focused mainly on global DNA methylation differences while others have quantified specific methylation differences for imprinted genes, transposable elements and DNA repair enzymes. Findings of global DNA hypomethylation and LINE-1 hypomethylation suggest that epigenetic alterations may disrupt neural tube closure. However, current research does not support a linear relation between red blood cell folate concentration and DNA methylation. Further studies are required to better understand the interaction between folate, DNA methylation changes and NTDs.

Methylome analysis for spina bifida shows SOX18 hypomethylation as a risk factor with evidence for a complex (epi)genetic interplay to affect neural tube development

“…This variant is known to lead to hyperhomocysteinemia and global DNA hypomethylation [ 2 – 4 ]. This association led to the hypothesis that folic acid prevents NTDs by stimulating DNA methylation [ 2 , 5 ]. To investigate whether changes in DNA methylation are involved in NTDs, different research groups have quantified global (e.g., via LINE-1 elements) or locus-specific (e.g., imprinted genes, transposable elements, DNA repair enzymes) DNA methylation for patients with NTDs using DNA from diverse types of tissues [ 5 ].…”

Deletion of BAF250a affects oocyte epigenetic modifications and embryonic development

“…Neural tube defect was reported in correlation with gene imprinting (Bai et al, 2014; Wang et al, 2017; Wu et al, 2013). Supplemental intake of formate during pregnancy was suggested as a method of preventing some neural tube defects owing to its function as methyl donor (Caffrey, McNulty, Irwin, Walsh, & Pentieva, 2018; Rochtus, Jansen, Van Geet, & Freson, 2015). Abnormal DNA methylation status in imprinting genes is related to diseases such as Beckwith‐Wiedemann Syndrome (Brzezinski et al, 2017; Chen, 2007; Cui et al, 2001; Sparago et al, 2004).…”

The effect of folic acid deficiency on FGF pathwayviaBrachyury regulation in neural tube defects

“…Establishment and maintenance of methylation patterns during embryogenesis have been consistently linked to NTDs (48, 49), and folate‐related one‐carbon metabolism plays a key role in these reactions (28, 50). Herein, observed alternation of Brachyury expression with low FA concentration in EBs implies its epigenetic regulation under FA conditions.…”