The imprinted Dlk1 gene in development and metabolism: a model for epigenetic control of developmental programming

Metabolic diseases are growing in world-wide prevalence; for example, over 1 million people died of diabetes in 2005. This figure is estimated to rise by 50% in the next ten years. Obesity is the most critical factor in the emergence of metabolic diseases; this too is growing in prevalence, particularly in the Western world. The pancreas is a key organ in the regulation of metabolism because it regulates how our bodies convert sugar into energy. Understanding the molecular mechanisms linking the abnormal development and function of the pancreas with metabolic disease, will help us understand this major health problem and contribute to improvements in disease prevention and the development of treatment strategies, in addition to contributing to our basic understanding of networks linking developmental and physiological processes.

Research investigating the molecular mechanisms underlying the pre- and post-natal development of systems regulating energy metabolism in mammals will contribute to our understanding of obesity, diabetes and the developmental origins of adult disease. The role of imprinted genes in pre-natal growth control has been apparent since their discovery, however more recently a role for imprinted genes in metabolic processes has emerged. Gene subject to genomic imprinting are predominantly expressed from one of the two parental chromosomes and are epigenetically regulated by parental-origin specific differential modifications to DNA and chromatin. Hence the dosage of imprinted gene products is dependent on regional epigenetic states rendering them vulnerable and adaptable. An imprinted domain located on mouse chromosome 12 contains the gene for a developmentally regulated atypical Notch-Delta signaling molecule, Delta-like homologue 1 (Dlk1/Pref1). Dlk1 contributes to both prenatal growth and post-natal metabolism and is expressed in the pancreas and peripheral tissues regulating glucose homeostasis. Using transgenic and knockout mouse models in which levels of Dlk1/Pref1 have been either lost or doubled, we have established an experimental paradigm for the investigation of the link between epigenetic regulation, genomic imprinting, prenatal development and post-natal metabolism. Here we propose an integrated programme of research that specifically investigates the relationship between levels of Dlk1 during development and the postnatal consequences for metabolism. Extending these studies, we propose to test the hypothesis that epigenetic control at imprinted domains can be affected by a compromised in utero environment. This research aims to contribute to our understanding of the developmental origins of adult disease.