Hepatocyte nuclear factor-4 prevents silencing of hepatocyte nuclear factor-1 expression in hepatoma x fibroblast cell hybrids

Hepatocyte nuclear factors-1 alpha (HNF1 alpha) and -4 (HNF4) are components of a liver-enriched transcription activation pathway which is thought to play a critical role in hepatocyte-specific gene expression, including activation of alpha 1-antitrypsin gene expression. HNF1 alpha, HNF4 and alpha 1-antitrypsin (alpha 1AT) genes are extinguished in hepatoma/fibroblast somatic cell hybrids, suggesting that fibroblasts contain a repressor-like activity. To determine the molecular basis for silencing of these genes in cell hybrids, ectopic expression of HNF1 alpha and HNF4 was used. Results show that constitutive expression of HNF4 prevents extinction of HNF1 a gene expression in hepatoma/fibroblast hybrids. In contrast, forced HNF1 alpha expression failed to prevent extinction of the HNF4 locus in cell hybrids. Likewise, the alpha 1AT gene remained silent in the presence of both HNF1 alpha and HNF4. These results suggest that extinction of HNF1 alpha is a simple lack-of-activation phenotype, whereas extinction of HNF4 and alpha 1AT loci is more complex, perhaps involving negative regulation.