Periconceptional supplementation of
folic acid to the diet of women is considered a great success for a public health intervention. Higher
folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has led to significant reduction in the incidence of
neural tube defects. Besides
birth defects,
folate deficiency has been linked to a variety of morbidities, most notably to increased risk for
cancer. However, recent evidence suggests that excess
folate may be detrimental - for
birth defect incidence or in the progression of
cancer. How
folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking
folate supplements, and thus experience a bolus of
folate on top of the status achieved by fortification. To characterize the response to a periconceptional regimen of supplementation with
folinic acid, we performed gene expression profiling experiments on uterus tissue of pregnant mice with either wildtype alleles or targeted disruption at the
folate receptor 4 locus. We observed that, depending on the genetic background,
folinic acid supplementation affects expression of genes that contribute to lipid metabolism,
protein synthesis, mitochondrial function, cell cycle, and cell activation. The extent of the response is strongly modulated by the genetic background. Finally, we provide evidence that
folinic acid supplementation in the mutant paradigm affects
histone methylation status, a potential mechanism of gene regulation in this model.