Impact of folic acid intake during pregnancy on genomic imprinting of IGF2/H19 and 1-carbon metabolism

Abstract

Folic acid is an essential component of 1-carbon metabolism, which generates methyl groups for DNA methylation. Disruption of genomic imprinting leads to biallelic expression which may affect disease susceptibility possibly reflected in high levels of S-adenosyl-homocysteine (SAH) and low levels of S-adenosyl-methionine (SAM). We investigated the association between folic acid supplementation during pregnancy and loss of imprinting (LOI) of IGF2 and H19 genes in placentas and cord blood of 90 mother-child dyads in association with the methylenetetrahydrofolate reductase (MTHFR) genotype. Pyrosequencing was used to evaluate deviation from monoallelic expression among 47 placentas heterozygous for H19 and 37 placentas and cord blood tissues heterozygous for IGF2 and H19 methylation levels of 48 placentas. We detected relaxation of imprinting (ROI) and LOI of H19 in placentas not associated with differences in methylation levels of the H19ICR. Placentas retained monoallelic allele-specific gene expression of IGF2, but 32.4% of cord blood samples displayed LOI of IGF2 and 10.8% showed ROI. High SAH levels were significantly associated with low H19 methylation. An interesting positive association between SAM/SAH ratio and high H19 methylation levels was detected among infants with low B₁₂ levels. Our data suggest profound differences in regulation of imprinting in placenta and cord blood; a lack of correlation of the methylome, transcriptome, and proteome; and a complex regulatory feedback network between free methyl groups and genomic imprinting at birth.-Tserga, A., Binder, A. M., Michels, K. B. Impact of folic acid intake during pregnancy on genomic imprinting of IGF2/H19 and 1-carbon metabolism.

Keywords: DNA methylation; MTHFR; epigenetics; folate; placenta.

Figure 1.

RBC folate levels in cord blood of infants whose mothers reported taking folic acid supplements before pregnancy (yes) and those who did not (no), stratified by MTHFR genotype. Restricted to mothers who reported taking folic acid during pregnancy.

Figure 2.

Pairwise Pearson (A) and partial (B) correlations between each biomarker, and among individuals with high (C) and low (D) B₁₂ (dichotomized at median 696 pg/ml). Width of line corresponds to the strength of the correlation (wider, stronger correlation); blue, positive correlation; red, negative correlation; solid line, significant correlation adjusting for multiple testing (Bonferroni); dotted line, not significant, after adjusting for multiple testing. Estimated correlations significant at P < 0.05 included in Supplemental Table 1.

Figure 3.

Spearman (ρ) and Pearson (R) correlations between 1-carbon metabolism biomarkers and H19 (A) and IGF2 (B) imprinting status. *P < 0.05.

Figure 4.

A) DNA methylation and imprinting status of H19 in placental tissue of mothers who took folic acid supplements before pregnancy (yes) and those who did not (no), stratified by MTHFR genotype. Restricted to mothers who took folic acid during pregnancy. B) Imprinting status of IGF2 and IGF2 protein level in cord blood of infants whose mothers took folic acid supplements before pregnancy (yes) and those who did not (no), stratified by MTHFR genotype. Restricted to mothers who took folic acid during pregnancy.