Grant: Operating Grant

The organization of genes in the human genome, the genetic blue print for a human being, has been described. There is evidence that this organization, which has occurred during evolution, has likely resulted in some cases where DNA sequences associated with one gene influence the use (expression) of a nearby gene. In simple terms, we are more than the sum of our individual genes and their expression. This has implications at a time when changes to the genome are being considered either as a research tool or for what is referred to in medicine as corrective gene therapy. We are using the human growth hormone gene family as a model system to understand the influence of nearby immune system-related and muscle-related gene sequences on the "normal" production of pituitary growth hormone. We are interested in how these sequences have come to be used to control when the growth hormone gene is opened up before we are born, why it is switched on only in the pituitary, and how it is able to respond to other hormones including steroids and insulin at different times. This certainly involves recognition of these DNA sequences by protein factors that interact with other proteins and are capable of changing the structure of specific regions of the chromosome. Identification and study of these sequences and associated proteins will increase our understanding of these processes, as well as when things start to wear out as with aging or go wrong as in conditions where insulin levels are high as with overeating or obesity. This is particularly important at a time when the growth hormone producing cell is being considered as a sensor for changes in our metabolism.