HEPATOCYTE NUCLEAR FACTOR-IV PREVENTS SILENCING OF HEPATOCYTE NUCLEARFACTOR-I EXPRESSION IN HEPATOMA X FIBROBLAST CELL HYBRIDS

Hepatocyte nuclear factors-1 alpha (HNF1 alpha) and -4 (HNF4) are comp onents of a liver-enriched transcription activation pathway which is t hought to play a critical role in hepatocyte-specific gene expression, including activation of alpha 1-antitrypsin gene expression. HNF1 alp ha, 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 f or silencing of these genes in cell hybrids, ectopic expression of HNF 1 alpha and HNF4 was used. Results show that constitutive expression o f HNF4 prevents extinction of HNF1 a gene expression in hepatoma/fibro blast hybrids. In contrast, forced HNF1 alpha expression failed to pre vent 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.