Gene promoter DNA methylation patterns have a limited role in orchestrating transcriptional changes in the fetal liver in response to maternal folate depletion during pregnancy

Abstract

ScopeEarly‐life exposures are critical in fetal programming and may influence function and health in later life. Adequate maternal folate consumption during pregnancy is essential for healthy fetal development and long‐term offspring health. The mechanisms underlying fetal programming are poorly understood, but are likely to involve gene regulation. Epigenetic marks, including DNA methylation, regulate gene expression and are modifiable by folate supply. We observed transcriptional changes in fetal liver in response to maternal folate depletion and hypothesized that these changes are concomitant with altered gene promoter methylation.Methods and resultsFemale C57BL/6J mice were fed diets containing 2 or 0.4 mg folic acid/kg for 4 wk before mating and throughout pregnancy. At 17.5‐day gestation, genome‐wide gene expression and promoter methylation were measured by microarray analysis in male fetal livers. While 989 genes were differentially expressed, 333 promoters had altered methylation (247 hypermethylated, 86 hypomethylated) in response to maternal folate depletion. Only 16 genes had both expression and methylation changes. However, most methylation changes occurred in genomic regions neighboring expression changes.ConclusionIn response to maternal folate depletion, altered expression at the mRNA level was not associated with altered promoter methylation of the same gene in fetal liver.

Maternal folate depletion during early development and high fat feeding from weaning elicit similar changes in gene expression, but not in DNA methylation, in adult offspring

“…Whilst we observed simultaneous changes in gene expression and promoter DNA methylation in response to both nutritional exposures investigated, we found no significant overlap between gene lists for which expression and promoter methylation were altered in response to a given exposure. These data corroborate our previous findings in the fetal liver in response to maternal folate depletion [66], and data from other studies reporting non-synonymous changes in gene expression and promoter DNA methylation [69][70][71][72]. However, as previously explored [66], we used PGE analysis to find regions of the genome enriched for changes in gene expression and promoter DNA methylation in response to maternal low folate and high fat intake post-weaning to test the hypothesis that methylation status of a gene promoter may not influence the expression of that specific gene but could influence expression of a neighbouring gene(s), as has been demonstrated by others [73].…”

“…in response to maternal folate depletion, 1859 genes were differentially expressed and 201 gene promotors differentially methylated; in response to high fat intake from weaning, 1532 genes were differentially expressed and 324 gene promotors differentially methylated). We have previously reported that folate depletion during pregnancy evoked approximately three times more changes in expression than in DNA methylation (expression of 989 genes v. methylation of 333 gene promoters) in the fetal liver . Others have reported genome‐wide, but also relatively small, changes in DNA methylation in the liver of rat offspring from dams fed a high‐fat diet (45% of energy from fat) throughout gestation and lactation and to the offspring from weaning until 12 weeks of age .…”

“…However, as previously explored [66], we used PGE analysis to find regions of the genome enriched for changes in gene expression and promoter DNA methylation in response to maternal low folate and high fat intake post-weaning to test the hypothesis that methylation status of a gene promoter may not influence the expression of that specific gene but could influence expression of a neighbouring gene(s), as has been demonstrated by others [73]. For most regions of promoter methylation change, we observed gene expression changes in neighbouring genomic regions that support our hypothesis that promoter methylation change may regulate gene regulation through cis-acting enhancer mechanisms [66,73]. However, this contention requires further testing.…”

“…in response to maternal folate depletion, 1859 genes were differentially expressed and 201 gene promotors differentially methylated; in response to high fat intake from weaning, 1532 genes were differentially expressed and 324 gene promotors differentially methylated). We have previously reported that folate depletion during pregnancy evoked approximately three times more changes in expression than in DNA methylation (expression of 989 genes v. methylation of 333 gene promoters) in the fetal liver [66,67].…”

Nutrition, epigenetics and health through life

“…) but, at least for folate restriction, alterations in DNA methylation do not appear to correspond directly with changes in gene expression in the fetal liver (McKay et al . ).…”