Selective loss of the hepatic phenotype due to the absence of a transcriptional activation pathway.

Liver-enriched trans-acting factors hepatocyte nuclear factor-1 alpha (HNF1 alpha) and -4 (HNF4) are components of a transcriptional activation pathway that is thought to play a major role in hepatic gene activation. We previously described the isolation and characterization of distinct classes of hepatoma variants which lack the HNF4-->HNF1 alpha pathway (1). In order to determine the influence of the HNF4-->HNF1 alpha pathway on hepatic gene expression, genetic rescue experiments were done using hepatoma variant line H11 as a model system. Results suggest that this pathway is required for basal expression of a number of endogenous hepatocyte-specific genes. Complementation groups were established by fusion of H11 cells with other variant lines. Lastly, introduction of human chromosome 20 (containing the HNF4 locus) or randomly-marked human chromosomes into H11 cells failed to rescue the hepatic phenotype, suggesting that what appears to be a 'simple' defect may involve multiple genetic loci.