Project:


DNA Methylation, Developmental Programming and Cellular Memory: The Molecular Consequences of Folate Depletion In Utero

From February 2009 to January 2012
Project Leader(s): Prof John Mathers, Dr. Dianne Ford

An accumulating body of evidence supports the premise that nutritional deprivation in utero has lifelong consequences for health, including a predisposition to obesity, cardiovascular disease and type 2 diabetes, particularly in association with a plentiful food supply post-weaning.

Thus, it is presumed that nutritional status in utero is recorded and remembered in a manner that programmes the foetus to use nutrients in a way that improves survival when the nutrient supply is poor but to be adapted inappropriately to a plentiful or excessive intake. Epigenetic processes, including DNA methylation, provide a compelling mechanism for such effects, manifest through influences on gene expression.

Our preliminary data reveal that folate depletion in utero in the mouse did not affect weight at weaning but increased the weight of offspring at 100 d and induced global DNA hypomethylation in liver and affected expression of multiple genes in foetal liver. These observations provide the impetus to examine in detail the influence of this nutritional stress on adiposity and on the methylation and expression of specific genes.

Our hypotheses are that:

  1. folate depletion in utero predisposes mice to increased weight and abdominal adiposity in adulthood, exacerbated by a high-fat post-weaning diet and
  2. the effect is mediated through the methylation of specific genes, which affects expression through transcription factor binding.

These hypotheses will be investigated through measuring the effect of folate depletion in utero in mice, followed by a control or high-fat post-weaning diet, on weight gain and adiposity and by examining effects at late gestation on DNA methylation in liver, using a microarray- based approach, and on gene expression and DNA methylation at 180 d. Effects of promoter methylation on gene expression and transcription factor binding will be investigated for selected differentially methylated and expressed genes using in vitro molecular approaches.

Staff

Professor Dianne Ford
Professor of Molecular Nutrition

Professor John Mathers
Professor of Human Nutrition