Epigenetic regulation of gene expression as a mechanism of nutritional programming and developmental origins of health and disease

The diet of an individual has important health issues at any stage of life - 'we are what we eat' after all. However, there is evidence to suggest that the diet of a pregnant woman is particularly important as it has major long-term implications on the health of her offspring - so, in some ways 'we also are what our mothers ate during pregnancy'. Normal term babies born from mothers with poor nutrition during pregnancy usually have a low weight. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing various common diseases such as diabetes, hypertension and heart disease in adulthood. The underlying causes of the relationship between poor early growth and disease in adulthood are not known, but we believe that the quality of the diet of women during pregnancy is critically important. Many of our attempts to decipher mechanisms of human diseases both rely and benefit from studying animal models. We have shown in a rodent model that if pregnant animals have too little protein during pregnancy their babies are small at birth and develop diabetes in adulthood. We have identified important genes in the pancreas that are expressed at low levels in the offspring of protein-restricted mothers compared to control animals. We now plan further to study these animals to understand how a restricted diet is able to perturb expression of key genes involved in pathogenesis of diabetes. We are particularly interested in studying epigenetic mechanisms - that is mechanisms able to change activity of a gene without altering its DNA sequence - that could be triggered by nutritional changes during pregnancy. We also want to know more precisely at which time/s during pregnancy the quality of the mother's diet is most important for giving birth to healthy babies. This will enable us to both identify at risk individuals and to develop intervention strategies to improve the health of both the pregnant women and their offspring.

The human baby responds and adapts to the nutrients it receives during gestation and lactation in a variety of ways. These adaptations include metabolic and endocrine changes that may lead to life-long changes in the function and structure the body - a concept which has been termed fetal programming. The suggestion is that the baby receives from its mother a forecast of the nutritional environment it will receive after birth and modifies its metabolism, whole body physiology and growth trajectory appropriately to maximise its chances of survival postnatally. However these adaptations become detrimental if the conditions after birth are not the same as the ones encountered during early life. The inappropriate programming results in a considerably higher susceptibility to developing chronic diseases of adult life. This Developmental Origins of Health and Disease hypothesis proposes that disorders such as heart disease and type 2 diabetes may result from an imbalance between the environment experienced in utero and that experienced postnatally. This hypothesis has been supported by numerous epidemiological studies which have shown an association between low birth weight and later disease and also by studies in animals. The dominant research focus to date has been the defining of the physiological adaptations and metabolic changes in both human and animal studies. However, very few studies have addressed the molecular mechanisms by which a phenomenon that occurs in utero has a phenotypic consequence many years later. Epigenetics refers to covalent modifications of DNA and core histones which are heritable and affect genome function (transcription, recombination, replication) without altering the nucleotide sequence of DNA. Epigenetic mechanisms are essential for development and differentiation and create a 'memory' of cell identity. Importantly, epigenetic modifications can be modulated by nutritional factors and can act as reversible switches of gene expression to heritably maintain specific genomic regions in a transcriptionally silent or active state. Epigenetic regulation of gene expression is therefore an attractive candidate mechanism for fetal programming because it confers and maintains cellular 'memory' for many cell divisions. The aim of this proposal is to establish a mechanistic link between maternal diet during pregnancy, epigenetic states of the genome and the developmental origins of adult disease. Using an integrated approach combining molecular biology, whole animal nutritional programming and functional genomics, epigenomics on a defined cell type, the pancreatic beta cell, we will address the following issues. Firstly, we will establish if the epigenetic state of the genome can be altered due to nutritional programming in utero and if such changes can explain programmed changes in gene expression. Secondly, we will identify the critical time windows by which epigenetic memory and gene activity are established by fetal programming. Finally, we will manipulate DNA methylation of key metabolic genes in vitro and profile the transcriptional and metabolic consequences. We will achieve these aims using our well established maternal protein restriction model of fetal programming. Understanding the mechanisms involved in intrauterine nutritional programming could ultimately lead to diagnosis, prevention and potential treatment of long term effects of maternal diet on adult health.