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

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

Departments of ^*Microbiology and Immunology, and ^†Pathology and Laboratory Medicine, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0298

Edited by Shirley M. Tilghman, Princeton University, Princeton, NJ, and approved August 1, 2000 (received for review June 23, 2000)

Abstract

α-Fetoprotein (AFP) transcription is activated early in hepatogenesis, but is dramatically repressed within several weeks after birth. AFP regulation is governed by multiple elements including three enhancers termed EI, EII, and EIII. All three AFP enhancers continue to be active in the adult liver, where EI and EII exhibit high levels of activity in pericentral hepatocytes with a gradual reduction in activity in a pericentral-periportal direction. In contrast to these two enhancers, EIII activity is highly restricted to a layer of cells surrounding the central veins. To test models that could account for position-dependent EIII activity in the adult liver, we have analyzed transgenes in which AFP enhancers EII and EIII were linked together. 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 this negative activity to a 340-bp fragment. This suggests that enhancer III may be involved in postnatal AFP repression.

Footnotes

↵ ‡ To whom reprint requests should be addressed. E-mail: bspear{at}pop.uky.edu.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.200290397.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.200290397
Abbreviations:

AFP,

α-fetoprotein;

MER,

minimal enhancer region;

βgl,

β-globin;

GAPDH,

glyeraldehyde-3-phosphate dehydrogenase;

HNF,

hepatocyte nuclear factor