Methylation variation atIGF2differentially methylated regions and maternal folic acid use before and during pregnancy

Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort

“…Hypermethylation of the H19 DMR has been linked to relaxation of imprint controls, increased transcription and translation of the potent IGF2 growth mitogen, 58 and higher birth weight. 59 Our findings are consistent with those of previous studies in which FA intake before or/and during pregnancy or folate levels were associated with DNA methylation differences of a similar magnitude at this imprinted domain [46][47][48][49]60 and early childhood obesity. [61][62][63] Similar to the IGF2/H19 imprinted domain where IGF2 and H19 are reciprocally imprinted, the DLK1 and MEG3 genes, located on chromosome 14q32.2, are also reciprocally imprinted.…”

“…However, methylation profiles at these DMRs in fractionated polymorphonuclear and mononuclear cells were comparable between these cell fractions, suggesting that DMR methylation profiles measured using unfractionated umbilical cord blood may not sizably differ by cell type. 47,73 Furthermore, DNA methylation in the regions examined was comparable in multiple tissues representing the three germ layers in human conceptal tissues. 73 Lastly, at the well-characterized IGF2/H19 IC, inverse associations have been reported for DMR methylation and in utero FA exposure using DNA methylation measurements from umbilical cord endothelial cells, 48 placenta 48 and umbilical cord leukocytes.…”

“…73 Lastly, at the well-characterized IGF2/H19 IC, inverse associations have been reported for DMR methylation and in utero FA exposure using DNA methylation measurements from umbilical cord endothelial cells, 48 placenta 48 and umbilical cord leukocytes. [47][48][49] The main limitation of this study is the relatively small sample size for maternal pre-pregnancy obesity-and race/ethnic-specific analyses to disentangle the role of maternal obesity from that of race/ethnicity in the associations between maternal folate, DMR methylation and birth weight. In addition, although the goal was to determine the extent to which periconceptional folate availability altered DNA methylation levels, some maternal blood from which folate levels were measured, was collected after 120 d gestation, the average life span of a red blood cell.…”

“…In humans, differences in DNA methylation of the differentially methylated regions (DMRs) regulating the imprinted expression of insulin like growth factor-2 (IGF2), were reported in individuals exposed to FA during the periconceptional 46 and prenatal periods. 47,48 However, historical reports of self-reported FA intake may be fraught with recall concerns and do not account for individual variation in diet and metabolism. Higher IGF2 and lower PEG3 DMR methylation levels were recently reported in DNA from umbilical cord leukocytes of infants born to women with higher prenatal erythrocyte folate.…”

Developmental programming of the metabolic syndrome - critical windows for intervention

“…For example, supplementation with iron and folic acid in pregnancy has been shown to increase birthweight but this response was modified by maternal nutritional status, with infants born to women with better shortterm nutrition having greater birthweight response [164] . Whether there is an epigenetic basis to these observations similar to those reported for the rat models is not well established although it has been suggested that alterations at the H19 differentially methylated region is a likely mechanism by which folic acid risks and/or benefits are conferred in utero [165] .…”