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 PA H is independent of glucocorticoids and/or cAMP in contrast to the mouse ge ne which is not only highly inducible but dependent upon hormones for expre ssion. Nevertheless, the two genes do exhibit similarities: DNaseI hypersen sitive sites are identically located in the regulatory regions, and the seq uences around these sites are partially conserved and associated with regul atory elements sharing similar function. In transient transfections, the hu man 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 b oth genes have enhancer activity that depends upon the liver-enriched trans cription 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 g ene activity in transient transfection assays in Pah-expressing hepatoma ce lls, this enhancer could be required in both species for activation during development. (C) 2001 Elsevier Science B.V. All rights reserved.