Effect of Maternal and Post-Weaning Folate Supply on Gene-Specific DNA Methylation in the Small Intestine of Weaning and Adult Apc+/Min and Wild Type Mice

Elizabeth A Williams,Jill A Mckay,John C Mathers

doi:10.3389/fgene.2011.00023

Abstract

Increasing evidence supports the developmental origins of adult health and disease hypothesis which argues for a causal relationship between adverse early life nutrition and increased disease risk in adulthood. Modulation of epigenetic marks, e.g., DNA methylation and consequential altered gene expression, has been proposed as a mechanism mediating these effects. Via its role as a methyl donor, dietary folate supply may influence DNA methylation. As aberrant methylation is an early event in colorectal cancer (CRC) pathogenesis, we hypothesized low maternal and/or post-weaning folate intake may influence methylation of genes involved in CRC development. We investigated the effects of maternal folate depletion during pregnancy and lactation on selected gene methylation in the small intestine of wild type (WT) and Apc+/Min mice at weaning and as adults. We also investigated the effects of folate depletion post-weaning on gene methylation in adult mice. Female C57Bl6/J mice were fed low or normal folate diets from mating with Apc+/Min males to the end of lactation. A sub-set of offspring were killed at weaning. Remaining offspring were weaned on to low or normal folate diets, resulting in four treatment groups of Apc+/Min and WT mice. p53 was more methylated in weaning and adult WT compared with Apc+/Min mice (p > 0.001). Igf2 and Apc were hypermethylated in adult Apc+/Min compared with WT mice (p = 0.004 and 0.012 respectively). Low maternal folate reduced p53 methylation in adults (p = 0.04). Low post-weaning folate increased Apc methylation in Apc+/Min mice only (p = 0.008 for interaction). These observations demonstrate that folate depletion in early life can alter epigenetic marks in a gene-specific manner. Also, the differential effects of altered folate supply on DNA methylation in WT and Apc+/Min mice suggest that genotype may modulate epigenetic responses to environmental cues and may have implications for the development of personalized nutrition.

Highlights

The developmental origins of health and disease (DOHaD) hypothesis proposes that exposures during early life modulate disease risk in adulthood
At weaning there was no difference in percentage methylation at the Igf2, p16, or Apc loci in Apc+/Min compared with wild type (WT) mice but the p53 locus was significantly (p < 0.001) more methylated in WT mice (Figure 1)
EFFECTS OF LOW MATERNAL DIETARY FOLATE ON GENE-SPECIFIC DNA METHYLATION No significant effects of low maternal dietary folate during pregnancy and lactation were observed on DNA methylation at the loci investigated in weaning mice

Summary

Introduction

The developmental origins of health and disease (DOHaD) hypothesis proposes that exposures during early life modulate disease risk in adulthood. There is substantial evidence for an association between lower birth weight and increased risk of type 2 diabetes, coronary heart disease, and hypertension, which has been attributed to poor nutrition in utero (Barker, 2004). These observations indicate the potential for a degree of plasticity during development which allows the fetal phenotype to be altered in response to environment cues (Bateson et al, 2004) in ways that may prepare it for the anticipated post-natal environment (Gluckman et al, 2005). DNA methylation, the most commonly investigated epigenetic mark, can be altered in offspring in response to maternal nutrition and these changes are associated with changes in gene expression and in the phenotype of the progeny (Waterland and Jirtle, 2003; Lillycrop et al, 2005; Dolinoy et al, 2006)

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