Single-base resolution of mouse offspring brain methylome reveals epigenome modifications caused by gestational folic acid

Abstract

BackgroundEpigenetic modifications, such as cytosine methylation in CpG-rich regions, regulate multiple functions in mammalian development. Maternal nutrients affecting one-carbon metabolism during gestation can exert long-term effects on the health of the progeny. Using C57BL/6 J mice, we investigated whether the amount of ingested maternal folic acid (FA) during gestation impacted DNA methylation in the offspring’s cerebral hemispheres. Reduced representation bisulfite sequencing at single-base resolution was performed to analyze genome-wide DNA methylation profiles.ResultsWe identified widespread differences in the methylation patterns of CpG and non-CpG sites of key developmental genes, including imprinted and candidate autism susceptibility genes (P <0.05). Such differential methylation of the CpG and non-CpG sites may use different mechanisms to alter gene expressions. Quantitative real time reverse transcription-polymerase chain reaction confirmed altered expression of several genes.ConclusionsThese finding demonstrate that high maternal FA during gestation induces substantial alteration in methylation pattern and gene expression of several genes in the cerebral hemispheres of the offspring, and such changes may influence the overall development. Our findings provide a foundation for future studies to explore the influence of gestational FA on genetic/epigenetic susceptibility to altered development and disease in offspring.

Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal life

“…Indeed, periconceptional use of FA by women has been associated with increased methylation of IGF2 in very young offspring (Steegers-Theunissen et al 2009). In addition, very recently, maternal feeding with high levels of FA during pregnancy has been demonstrated to alter methylation status in the offspring of mice, particularly in white adipose tissue (Huang et al 2014) and in the brain, the latter with a sex dimorphism response (Barua et al 2014).…”

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended ‘male sex drive’ hypothesis

“…Indeed, sex-biased DNA methylation was reported for saliva, blood and brain samples of humans [16][17][18][19]. Sex-specific methylation patterns have been also observed in the brains of mice [20] and chicken [21]. A recent study on mice revealed that DNA methylation plays a key role in suppressing masculinization in the developing brain and allows the brain to preserve its original feminized form in female animals [22].…”

- A Prospective Study of Nutrition Education and Oral Nutritional Supplementation in Patients with Alzheimer’s Disease

“…Furthermore, Barua et al [16] suggested that the occurrence of such epigenetic changes during gestational development may impact methylation status of DNA in the offspring's brain and cause altered gene expression, and since gestational development involves a highly orchestrated regulation of gene expression, this gene dysregulation may affect brain development and may result in various neuropsychiatric conditons. Baura et al [17] identified substantial differently methylated regions (DMRs) in the the cerebral hemispheres of mice offspring of mothers on high folic acid intake as compared to offspring of mice on low maternal folic acid diet. These results support the findings of numerous studies that show that abnormalities in the frontal lobes impact brain development and autism [20][21][22][23][24].…”

“…Figure 1 illustrates how the folate cycle facilitates nucleic acid synthesis and is responsible for transfer of 1-C methyl groups to DNA and proteins [16]. Methyl groups added onto cytosine residues in the promoter region CpGs in genomic DNA are central to regulation of gene expression [17,18]. Recent investigations have led to suggestion that children with autism may have altered folate or methionine metabolism resulting in hypotheses that the folate-methionine cycle may play a key role in the etiology of autism.…”