Gavin Kelsey
Imprinted genes: function and regulation
Genomic imprinting is a specialised form of gene regulation in mammals that results in the silencing of one copy (allele) of specific genes, according to whether the allele comes from the father or mother. Imprinted expression is the outcome of multiple developmental events: differential marking of sequences in the male and female germlines; persistence of these marks in somatic tissues of the developing embryo and into adult life; and translation of these marks into different states of gene activity. This memory of parental origin is a classic example of epigenetic regulation.
Around 70 imprinted genes have been identified in the mouse genome, many of which are similarly imprinted in humans. Imprinting has crucial roles in growth and development of the fetus, in the physiology of the neonate and continues to influence our metabolism and behaviour into adult life. Deliberate silencing of one gene copy risks exposing genes to the effects of mutation and other lesions, and imprinted gene defects are increasingly recognised as a source of developmental, cancer and metabolic disease syndromes in humans.
We are interested in understanding the function of specific imprinted genes, and this is exemplified by our work on the Gnas cluster. Careful dissection of the functions of the genes in this cluster has revealed how different imprinted genes interact in common physiological pathways and suggest that the correct balance of activities of imprinted genes is essential for normal control of metabolism and optimal health. Understanding the function of the genes in this imprinted cluster also helps us to make rational predictions about how imprinting is regulated and to understand why this form of epigenetic regulation has evolved in mammals.
A key question is what dictates which of our 30,000 genes becomes imprinted. Recent work in our group has identified a novel role for transcription in helping to establish the epigenetic marks that define imprinted genes in germ cells.
