Mice lacking the liver-enriched homeoprotein hepatocyte nuclear factor 1alpha (HNF1α) display phenylketonuria due to complete inactivation of the phenylalanine hydroxylase(PAH) gene. In the June issue of Molecular and Cellular Biology, Viollet et al. define the factors necessary for reactivation of the silenced PAH gene (Mol Cell Biol 2001, 21:3662-3670). They investigated the effects of HNF1α re-expression (using a recombinant adenoviral vector), DNA methylation and histone acetylation on PAH expression in cultured hepatocytes from HNF1 knockout mice. HNF1α expression could partially restore PAH gene transcription in embryonic hepatocytes, but not in newborn or adult liver cells. Furthermore, drugs that inhibit DNA methylation or histone deacetylase could synergize to reactivate PAH expression. Hence, gene regulation by HNF1α during liver development is associated with the control of methylation and chromatin remodelling at the PAH promoter.