Nutrition and early life programming: exploring epigenetic mechanisms

Nutritional stresses in early life have long-lasting effects on health. Rapid growth in early postnatal life has been linked to increased incidence of common diseases such as obesity, cardiovascular disease and type 2 diabetes in later life. The mechanisms that link early post-natal nutrition with later ill health have not been well defined. Infants born preterm are encouraged to gain weight rapidly but this has important implications for adult health. By studying children who were born preterm, now aged 10-12 years, who participated in a post-natal nutritional trial we can glean important information not only about the health consequences of different infant feeding regimen, but also about the molecular mechanisms involved. This project aims to examine the molecular mechanisms that allow early nutrition to be 'memorised' at a cellular level. The genome is 'marked' in response to nutritional exposures and these markings can induce stable changes in which genes are switched on and switched off. Epigenetics refers to the decoration of the genome by these chemical markings and is an emerging field of post-genomic science. New technologies will be used to study epigenetic markings and gene expression in 120 children born preterm. These children took part in a nutritional trial and were fed one of three different diets from 36 weeks gestation to 6 months of age. Their growth and development has been followed over the last 10-12 years. Changes observed in epigenetic status and in gene expression will be related to differences in the health of the children, such as body composition, blood pressure, glucose and insulin levels and levels of hormones involved in fat metabolism. This project will use new tools in biotechnology and bioinformatics to study how nutrition influences the genome and how this may have long lasting effects on health.

This proposal responds to the current BBSRC Joint Committee Priority on Developmental Origins of Optimal Health. It will examine variation in epigenetic marking, gene expression and biomarkers of metabolic health in children exposed to markedly different nutritional regimen in very early postnatal life and contribute to understanding the mechanisms linking adverse exposures in early life with common diseases such as obesity, cardiovascular disease and type 2 diabetes in later life. Nutritional stresses in early life have long-lasting effects on metabolism and health. Through work on animal models, epigenetic phenomena have been identified as a providing a potential candidate mechanism to explain this association. Early postnatal life offers a 'critical window' during which nutritional stresses can programme the subsequent health of an individual. By studying a cohort of infants born preterm and who participated in a randomised nutritional intervention trial of preterm and term formula feeding, we aim to investigate the role of epigenetic events in mediating persistent differential gene expression and altered health in children 10-12 years later. Epigenetic markings refer to chemical modifications to DNA and histone proteins that regulate transcriptional activity. This study will focus on DNA methylation. Techniques to detect and compare DNA methylation on a large scale have only been developed in recent years. This study will employ a microarray approach to screen for differences in DNA methylation and gene expression. Methylation differences at selected loci will be verified by quantitative, sequenced-based analysis using Pyrosequencing technology. Differential gene expression at selected loci will be quantified and verified using Real-Time PCR. This work exploits new high throughput technologies and builds on ongoing work in nutritional epigenomics.