1. Multiple Hepatocyte-Enriched Nuclear Factors Function in the Regulation of Transthyretin and α1-Antitrypsin Genes
- Author
-
Costa, R H, Grayson, D R, and Darnell, J E
- Subjects
Binding Sites ,Base Sequence ,Nuclear Proteins ,nutritional and metabolic diseases ,DNA ,Cell Biology ,DNA-Binding Proteins ,Mice ,Enhancer Elements, Genetic ,Gene Expression Regulation ,Liver ,alpha 1-Antitrypsin ,Animals ,Humans ,Prealbumin ,Molecular Biology ,Research Article - Abstract
Transthyretin (TTR) and alpha 1-antitrypsin (alpha 1-AT) are expressed at high levels in the liver and also in at least one other cell type. We report here a detailed analysis of the proximal regulatory region of the TTR gene, which has uncovered two new DNA-binding factors that are present mainly (or only) in hepatocytes. One of these new factors, hepatocyte nuclear factor 3 (HNF-3), binds to two sites that are crucial in TTR expression as well as to two additional sites in the alpha 1-AT proximal enhancer region. The second new factor, HNF-4, binds to two sites in TTR that are required for gene activity. We had previously identified binding sites for another hepatocyte-enriched DNA-binding protein (C/EBP or a relative thereof), and additional promoter-proximal sites for that protein in both TTR and alpha 1-AT are also reported here. From these results it seems clear that cell-specific expression is not simply the result of a single cell-specific factor for each gene but the result of a combination of such factors. The variation and distribution of such factors among different cell types could be an important basis for the coordinate expression of the TTR and alpha 1-AT genes in the liver or the discordant transcriptional activation of these genes in a few other cell types. The identification of such cell-enriched factors is a necessary prelude to understanding the basis for cell specificity.
- Published
- 1989