Rescue of the HNF4 -> HNF1 alpha pathway in hepatoma variant cells containing human chromosome 12

Expression of liver-enriched trans-acting hepatocyte nuclear factors 1 alph a (HNF1 alpha) and 4 (HNF4) is correlated with the hepatic phenotype in cul tured rat hepatoma cells. We have used a hepatoma variant cell line, H11, t hat specifically lacks the HNF4 --> HNF1 alpha pathway as a model to unders tand mechanisms controlling hepatic gene expression. We have introduced ran domly marked human chromosomes into H11 cells and have isolated a number of microcell hybrids that have rescued hepatic gene expression, including HNF 4, HNF1 alpha, and alpha 1-antitrypsin. Chromosomal analysis of cell. hybri ds showed that the rescued hepatic phenotype correlated closely with the pr esence of human chromosome 12p sequences. Although the gene encoding HNF1 a lpha is located on chromosome 12q24, its retention was not required to resc ue the hepatic phenotype. Thus, we suggest that a locus on human chromosome 12p plays an important role in maintenance of hepatic gene expression thro ugh activation of the HNF4 --> HNF1 alpha pathway. (C) 1998 Academic Press.