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

摘要

Hepatocyte nuclear factors-1α (HNF1α) 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 α1-antitrypsin gene expression. HNF1α, HNF4 and α1-antitrypsin (α1AT) 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 HNF1α and HNF4 was used. Results show that constitutive expression of HNF4 prevents extinction of HNF1α gene expression in hepatoma/fibroblast hybrids. In contrast, forced HNF1α expression failed to prevent extinction of the HNF4 locus in cell hybrids. Likewise, the α1AT gene remained silent in the presence of both HNF1α and HNF4. These results suggest that extinction of HNF1a is a simple lack-of-activation phenotype, whereas extinction of HNF4 and α1AT loci is more complex, perhaps involving negative regulation.