Conserved as well as divergent regulatory elements account for expression of the human and rodent phenylalanine hydroxylase genes.
We have uncovered a fundamental difference in the regulation of the rodent and the human phenylalanine hydroxylase (PAH) genes: expression of human PAH is independent of glucocorticoids and/or cAMP in contrast to the mouse gene which is not only highly inducible but dependent upon hormones for expression. Nevertheless, the two genes do exhibit similarities: DNaseI hypersensitive sites are identically located in the regulatory regions, and the sequences around these sites are partially conserved and associated with regulatory elements sharing similar function. In transient transfections, the human proximal promoter is tissue-specific and presents significant activity compared to the extremely low and ubiquitous activity of the mouse promoter. DNA fragments corresponding to the two upstream hypersensitive sites of both genes have enhancer activity that depends upon the liver-enriched transcription factor binding sites for hepatocyte nuclear factor (HNF) 1 and/or CCAAT/enhancer binding protein (C/EBP). While expression of the rodent gene relies upon two modules in the HSIII enhancer, one activated by HNF1 and C/EBP and the other required for the hormone response, the human equivalent has conserved only the liver-specific transcription factor binding module. Even though the more proximal enhancer is not necessary for full reporter gene activity in transient transfection assays in Pah-expressing hepatoma cells, this enhancer could be required in both species for activation during development.
Bristeau
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A
Unité de Génétique de la Différenciation, FRE 2364, Centre National de la Recherche Scientifique, Département de Biologie Moléculaire, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France.
Catherin
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A
Weiss
M C
MC
Faust
D M
DM
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D015500:Chloramphenicol O-Acetyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D000242:Cyclic AMP / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D003850:Deoxyribonuclease I / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014644:Genetic Variation; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C496496:Hnf1b protein, mouse; D006728:Hormones; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D003907:Dexamethasone; D004247:DNA; D000242:Cyclic AMP; D010651:Phenylalanine Hydroxylase; D015500:Chloramphenicol O-Acetyltransferase; D003850:Deoxyribonuclease I