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Volume 271, Number 46, Issue of November 15, 1996 pp. 29502-29512
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Regions Flanking Exon 1 Regulate Constitutive Expression of the Human Antithrombin Gene

(Received for publication, January 26, 1996, and in revised form, June 11, 1996)

Françoise A. Fernandez-Rachubinski ^§ , Joel H. Weiner and Morris A. Blajchman

From the  Department of Pathology, McMaster University, Hamilton, Ontario L8N 3Z5 and the Departments of ^§ Medicine and  Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

We have identified cis-acting elements and trans-acting factors that regulate constitutive expression of the human antithrombin gene. The activity of the sequences flanking the first exon of the gene was investigated using a luciferase-based reporter assay in transiently transfected HepG2, COS1, BSC40, and HeLa cells. Deletion analysis allowed the mapping of two elements able to promote antithrombin gene transcription in HepG2 and COS1 cells. The first element is located upstream of the first exon (150/+68 nucleotides). The second element is in the first intervening sequence (+300/+700 nucleotides) and functions in an orientation opposite to that of the first. Footprint analysis showed three protected areas in the 5 upstream element at 92/68 (element A), 14/+37 (element B), and 126/100 nucleotides (element C). These elements acted as enhancers in luciferase reporter assays. Gel retardation analysis demonstrated that two liver-enriched transcription factors, hepatocyte nuclear factor 4 (HNF4) and CCAAT enhancer-binding protein (C/EBPa), bound to the 5 upstream element. HNF4 bound to elements A and C, whereas C/EBPa bound to element B. Element A also interacted with the ubiquitous nuclear hormone receptors chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1), thyroid hormone receptor  (TR), peroxisome proliferator-activated receptor (PPAR), and retinoid X receptor  (RXR). In HepG2 and BSC40 cells, HNF4, C/EBP, and RXR activated luciferase expression from a reporter construct containing the 5-upstream minimal antithrombin gene promoter, while COUP-TF1, TR, and HNF3 ( or ) repressed such expression. Our results show that constitutive expression of the human antithrombin gene depends in part upon the interplay of these transcription factors and suggest that signaling pathways regulated by these factors can modulate antithrombin gene transcription.

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