In pregnant women, intervention with folic acid triggers an alteration in DNA methylation that influences neural target genes via two different mechanisms.

This study aimed to determine the biological mechanism of continued use of folic acid after 1st trimester of pregnancy on neurocognitive functioning in children.

Samples were used from the trial of folic acid use in the 2nd and 3rd trimesters. In this trial, profound enhancement in cognitive and psychosocial performance were shown in children from females who received 400 µg/day of folic acid during pregnancy in comparison with placebo.

The methylation patterns were examined from cord blood utilizing EPIC array that covers around 850,000 cytosine-guanine sites throughout genome. Utilizing pyrosequencing, the genes displaying substantial differences were verified. To determine the impact on transcription, mechanistic approaches were utilized in vitro.

Continued use of folic acid by pregnant women in the 2nd and 3rd  trimesters elicited genome-wide hypomethylation in the cord blood of their offspring, thus adding to the supporting evidence for continued folic acid use throughout later gestation and its link with optimal neurodevelopment of children.

Folic acid supplementation led to substantial differences in methylation, majorly in brain-related genes. Additional assessment depicted that these genes segregate into 2 groups. The methylation alterations at promoters were crucial to regulate transcription in the 1st group, that incorporated the CES1 gene. The 2nd  group with a special bimodal profile, low promoter and high gene body methylation was detected too.

Loss of methylation in gene body (in second group) was related to transcription reduction. This group incorporated the dopamine receptor regulator PDE4C and the PRKAR1B/HEATR2 genes. Methylation in the cord blood exhibited a remarkable symmetry with profiles of methylation observed in a published data set of late gestation samples of the fetal brain.

An association exists between folic acid use in later pregnancy, better cognitive performance and epigenetic alterations at genes implicated in improved brain function.