Hepatocyte nuclear factor 4alpha (HNF4alpha) is essential for the establishment and maintenance of liver-specific gene expression. The HNF4alpha gene codes for several isoforms whose developmental and physiological relevance has not yet been explored. HNF4alpha1 and HNF4alpha7 originate from different promoters, while alternative splicing in 3' leads to HNF4alpha2 and HNF4alpha8, respectively. HNF4alpha7/alpha8 were abundantly expressed in embryonic liver and fetal-like hepatoma cells. HNF4alpha1/alpha2 transcripts were up-regulated at birth and represented the only isoforms in adult-like hepatoma cells. In line with its expression profile, HNF4alpha7 activated more avidly than HNF4alpha1 reporter plasmids for genes that are expressed early. The expression patterns of both isoforms together with the differences observed in their transcriptional activities provide elements accounting for fine-tuning of the activity of HNF4alpha. The sequential expression of HNF4alpha7/alpha8 and HNF4alpha1/alpha2 during mouse liver development is the only modification in liver-enriched transcription factors thus far recorded, which parallels the transition from the fetal to the adult hepatic phenotype.
In fetal liver, bipotential hepatoblasts differentiate into hepatocytes and bile duct cells (cholangiocytes).
Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver.Genetic analysis of hepatoma-derived cell lines revealed, many years ago, that expression of differentiated functions is regulated in trans by mechanisms whose final effects are negative (extinction) or positive (activation) (78). More recent studies of these hepatoma lines further showed that maintenance of the hepatic phenotype is an active process operating at the level of transcription (21,42). By analysis of DNA sequences implicated in liver-specific transcription, the identification and cloning of members of four major families of liverenriched transcription factors (LETF) have been achieved. These families, each characterized by structurally related DNA binding domains, include the hepatocyte nuclear factor families HNF1, HNF3, and HNF4 and the CCAAT enhancer binding protein (C/EBP) family (13,82). Determination of the tissue distribution of these factors and analysis of their hierarchical relations led to the hypothesis that the combinatorial action of LETF together with the ubiquitous transcriptional machinery of the cell is necessary and maybe even sufficient for the maintenance of liver-specific gene transcription (30, 81). Indeed, the H4IIEC3 differentiated rat hepatoma cells and their derivatives that stably express an extensive set of adult hepatic functions express all the LETF identified to date, while in the rare dedifferentiated rat hepatoma cells that have lost expression of all these hepatic functions, HNF4 and HNF1 are systematically absent. In addition,...
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