International Mammalian Genome Society


The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G26 Multiple Regulatory Regions Control Postnatal Alpha-fetoprotein Repression in the Liver

David K. Peyton, Tennore Ramesh, Mei-Chuan Huang, and Brett T. Spear. Department of Microbiology and Immunology, University of Kentucky, College of Medicine, Lexington, KY 40536-0298

Alpha-fetoprotein (AFP) is expressed at high levels in the yolk sac and fetal liver and at low levels in the fetal gut. AFP transcription is dramatically repressed in the liver and gut at birth to levels that are barely detectable by postnatal day 28. This repression is reversible as the AFP gene can be reactivated during liver regeneration and in hepatocellular carcinomas. Previous studies in cultured cells and transgenic mice identified five distinct regions upstream of the AFP gene that control its expression. The promoter and three enhancers functioned as positive regulatory elements, whereas the repressor acted as a negative element. The promoter resides within the 250 bp directly adjacent to exon 1. The repressor, a 600 bp region located between -250 and -850, is required for postnatal AFP repression. Further upstream at -2.5, -5.0 and -6.5 kb are three enhancers termed Enhancer I (EI), EII, and EIII. These three enhancers are active, to varying degrees, in the three tissues where AFP is expressed.

We previously showed in transgenic mice that the AFP enhancers continue to be active in the adult liver in a position-dependent manner; EI and EII are most active in hepatocytes surrounding the central vein with a gradual reduction in activity towards the portal triad. EIII was active exclusively in one to two layers of cells around the central vein. This zonal control of gene expression in the adult liver has been observed for numerous genes that are expressed in the liver, but the basis for this regulation is not known. We show here that the highly restricted pattern of EIII activity is due to negative regulation in all hepatocytes except those encircling the central veins. This raises the possibility that EIII may contribute to postnatal AFP repression in all but pericentral hepatocytes.

Hepatic AFP and H19 mRNA levels in adult BALB/cJ mice are 10- to 15-fold higher than adult liver AFP mRNA levels in other mouse strains. This difference is controlled by an unlinked locus called Alpha-fetoprotein regulator-1 (Afr-1). In contrast to most transcriptional regulators in mammals that have been defined using biochemical strategies, Afr-1 was identified genetically. Our previous studies showed that Afr-1 regulation is independent of the AFP enhancers but requires the AFP promoter/repressor region. Here, we demonstrate that the AFP promoter, but not the repressor, is regulated by Afr-1. Based on the notion that Afr-1 functions as a repressor of adult liver AFP mRNA levels, these data indicate that the promoter is involved in postnatal AFP shut-off. Furthermore, we provide a high resolution map of the Afr-1 locus on mouse chromosome 15.

These studies indicate that postnatal AFP shut-off in the liver is not regulated solely by the repressor region but is rather controlled by multiple cis-acting elements. Identification of the factors that regulate these elements, including Afr-1, should help elucidate the basis of this control. These results also raise the possibility that postnatal AFP repression and position-dependent gene expression in the adult liver may be governed by a similar mechanism.

 


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