An enhancer element 6 kb upstream of the mouse HNF4alpha1 promoter is activated by glucocorticoids and liver-enriched transcription factors.
We have characterized a 700 bp enhancer element around -6 kb relative to the HNF4alpha1 transcription start. This element increases activity and confers glucocorticoid induction to a heterologous as well as the homologous promoters in differentiated hepatoma cells and is transactivated by HNF4alpha1, HNF4alpha7, HNF1alpha and HNF1beta in dedifferentiated hepatoma cells. A 240 bp sub-region conserves basal and hormone-induced enhancer activity. It contains HNF1, HNF4, HNF3 and C/EBP binding sites as shown by DNase I footprinting and electrophoretic mobility shift assays using nuclear extracts and/or recombinant HNF1alpha and HNF4alpha1. Mutation analyses showed that the HNF1 site is essential for HNF1alpha transactivation and is required for full basal enhancer activity, as is the C/EBP site. Glucocorticoid response element consensus sites which overlap the C/EBP, HNF4 and HNF3 sites are crucial for optimal hormonal induction. We present a model that accounts for weak expression of HNF4alpha1 in the embryonic liver and strong expression in the newborn/adult liver via the binding sites identified in the enhancer.
Bailly
A
A
Unité de Génétique de la Différenciation, FRE 2364 du CNRS, Institut Pasteur, 25 Rue du Dr Roux, 75724 Paris Cedex 15, France.
Torres-Padilla
M E
ME
Tinel
A P
AP
Weiss
M C
MC
D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites / Q000235:genetics; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051541:Hepatocyte Nuclear Factor 3-alpha; D051557:Hepatocyte Nuclear Factor 4; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D022763:CCAAT-Enhancer-Binding Protein-alpha; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D005938:Glucocorticoids; D051538:Hepatocyte Nuclear Factor 1-alpha; D051541:Hepatocyte Nuclear Factor 3-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D003907:Dexamethasone; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase