Position-dependent activity of alpha-fetoprotein enhancer element III in the adult liver is due to negative regulation

alpha-Fetoprotein (AFP) transcription is activated early in hepatogenesis. but is dramatically repressed within several weeks after birth. AFP regulat ion is governed by multiple elements including three enhancers termed EI. E II, and EIII. All three AFP enhancers continue to be active in the adult li ver, where EI and EII exhibit high levels of activity in pericentral hepato cytes with a gradual reduction in activity in a pericentral-periportal dire ction. In contrast to these two enhancers, EIII activity is highly restrict ed to a layer of cells surrounding the central veins. To test models that c ould account for position-dependent EIII activity in the adult liver, we ha ve analyzed transgenes in which AFP enhancers EII and EIII were linked toge ther. our results indicate that the activity of EIII is dominant over that of EII, indicating that EIII is a potent negative regulatory element in all hepatocytes except those encircling the central veins. We have localized t his negative activity to a 340-bp fragment. This suggests that enhancer III may be involved in postnatal AFP repression.