Genomic imprinting and the epigenetic control of developmental processes

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All the cells in our body are genetically identical and contain 46 chromosomes (23 pairs) where all of our genes are located - 23 chromosomes originally came from our mother's egg and 23 from our father's sperm. Thus, since the time of conception, a normal individual will have two copies of every gene. This application is about a process called Genomic Imprinting. Imprinting causes specific genes to be turned on (expressed) solely from the maternal or from the paternal copy rather than from both copies. It is a process that affects only about 1% of our genes. But control of gene dosage by imprinting is important during development, and when imprinting goes wrong this leads to growth defects, neurological syndromes and cancer. This grant explores the regulation, function and evolution of imprinting, so we can understand these disease processes better.We are interested in understanding mechanisms of imprinted expression. What makes an imprinted gene be expressed from one of the chromosomes in a pair rather than both of them? The process causing only the paternally inherited or the maternally inherited copy to be expressed, is an 'epigenetic' one. Epigenetics means 'on top of genetics' and the epigenetic state at an imprinted gene is manifested as chemical modifications that sit on the DNA at only one parental chromosome and not the other causing the gene located there to be expressed on one of the chromosomes and kept off on the other. Our first aim is designed to ask whether all imprinted genes are fully ON on one chromosome and fully OFF on the other, or whether some imprinted genes are expressed from both chromosomes but more from one chromosome and less from the other. This is important for understanding mechanisms of imprinting and whether more genes are imprinted than originally thought. This has implications for disease. In our second aim, we are interested in focusing on the function of a particularly important imprinted gene (Dlk1) that is able to act not only in an imprinted way, but also be expressed like other genes from both parental chromosomes. This is a remarkable gene whose dosage is very important in the brain and elsewhere in the body too. In fact, it also regulates the development of our fat, and controls metabolism. Interestingly there is another gene that looks very like this one (Dlk2); it is never imprinted and is the ancestor to Dlk1 which arose as a copy of Dlk2. Dlk2 only functions in the brain. In this set of experiments, we will study the relationship between these two genes, asking how and why one evolved from the other, why one is imprinted and the other not, and the extent to which they act in the same and in different pathways. Genes regulated by imprinting are very important for controlling growth and development in the womb and this has been extensively studied in the placenta which is an essential site of imprinted gene expression. However, since important nutritional events happen after birth too, we hypothesize that imprinted genes also regulate postnatal nutrition. In our third aim, we will ask whether the ability to feed milk to offspring via the mammary gland is also controlled by genomic imprinting. Since the mammary gland undergoes dramatic changes during pregnancy, lactation and upon weaning, it is likely that these changes are subject to epigenetic control. Hence the experiments outlined in this third aim will not only provide important knowledge about the development of the mammary gland and the exchange of nutritional resources between mother and baby, but might also provide useful insights into our understanding of the function, mechanism and evolution of the imprinting process.