The liver performs a number of different functions, producing many of the serum proteins, metabolic enzymes, acute-phase reactants, and detoxifying enzymes that serve to maintain homeostasis in an organism. These diverse functions require the coordinate regulation of numerous genes within the liver, and many genes must be expressed in response to developmental, hormonal, and environmental signals. Thus, the liver provides an ideal organ to study mechanisms of gene regulation. This proposal will investigate the regulation of the mouse alpha- fetoprotein (AFP) gene enhancer region. While AFP is the major serum protein in the mammalian fetus, the precise function of AFP is not known. It may be involved in the binding and transport of fetal hormones, bilirubin, and organic cations. AFP may also act as an immunosuppressant that protects the developing fetus from rejection by the maternal immune system. Despite our immunosuppressant that protects the developing fetus from rejection by the maternal immune system. Despite our lack of understanding regarding AFP function, this gene provides an excellent model system to investigate developmental and liver-specific transcriptional control. This proposal will address several fundamental questions. What is the molecular basis of liver- restricted enhancer activity? What is the basis of zonal control of gene expression in the adult liver? What trans-acting transcription factors are involved in the reprogramming of gene expression during liver regeneration? Liver disorders, many which are due to insufficient or inappropriate gene expression during liver disease, represent a major health concern. These experiments should elucidate further our understanding of transcription in the liver during normal and pathological conditions. In addition, the information derived from these studies may improve strategies to express foreign genes within the liver, a goal of many gene therapy trials.
