Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression.
Hepatocyte nuclear factor 4 (HNF-4) is a liver-enriched transcription factor and a member of the steroid hormone receptor superfamily. HNF-4 is required for the hepatoma-specific expression of HNF-1 alpha, another liver-enriched transcription factor, suggesting the early participation of HNF-4 in development. To prepare for further study of HNF-4 in development, the tissue-specific expression of the mouse HNF-4 gene was studied by analyzing the promoter region for required DNA elements. DNase-hypersensitive sites in the gene in liver and kidney tissues were found in regions both distal and proximal to the RNA start that were absent in tissues in which HNF-4 expression did not occur. By use of reporter constructs in transient-transfection assays and with transgenic mice, a region sufficient to drive liver-specific expression of HNF-4 was identified. While an HNF-1 binding site between bp -98 and -68 played an important role in the hepatoma-specific promoter activity of HNF-4 in transient-transfection assays, it was not sufficient for the liver-specific expression of a reporter gene in transgenic mice. Distal enhancer elements indicated by the presence of DNase I-hypersensitive sites at kb -5.5 and -6.5, while not functional in transient-transfection assays, were required for the correct expression of the mouse HNF-4 gene in animals.
Zhong
W
W
Laboratory of Molecular Cell Biology, Rockefeller University, New York, New York 10021.
Mirkovitch
J
J
Darnell
J E
JE
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D015342:DNA Probes / Q000235:genetics; D004268:DNA-Binding Proteins; D003850:Deoxyribonuclease I; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010750:Phosphoproteins; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015342:DNA Probes; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D012313:RNA; D003850:Deoxyribonuclease I