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The failure to transcribe the phenylalanine hydroxylase (PAH) gene in the liver of hepatocyte nuclear factor 1alpha (HNF1alpha)-deficient mice correlated with DNA hypermethylation and the presence of an inactive chromatin structure (M. Pontoglio, D. M. Faust, A. Doyen, M. Yaniv, and M. C. Weiss, Mol. Cell. Biol. 17:4948-4956, 1997). To evaluate the precise role played by HNF1alpha, DNA methylation, or histone acetylation in PAH gene silencing, we examined conditions that could restore PAH gene expression in HNF1alpha-deficient hepatocytes. We show that reactivation of PAH transcription can be achieved by reexpression of HNF1alpha in embryonic (i.e., embryonic day 12.5 [e12.5] to e13.5) hepatocytes but not in fetal (e17.5), newborn, and adult HNF1alpha-deficient hepatocytes. This defines a temporal competence window during which HNF1alpha can act to (re)program PAH gene transcription. We also show that PAH gene silencing can be partially relieved in HNF1alpha-deficient hepatocytes by treatment with the demethylating agent 5-azacytidine, even in the absence of HNF1alpha. Treatment using 5-azacytidine combined with trichostatin, a histone deacetylase inhibitor, resulted in a synergistic reactivation of the silenced PAH gene in adult hepatocytes, but this activity was not further increased by HNF1alpha reexpression. These results suggest that the HNF1alpha homeoprotein is involved in stage-specific developmental control of the methylation state and chromatin remodeling of the PAH gene.

molecular and cellular biology

Embryonic but Not Postnatal Reexpression of Hepatocyte Nuclear Factor 1α (HNF1α) Can Reactivate the Silent Phenylalanine Hydroxylase Gene in HNF1α-Deficient Hepatocytes