Expression of HNF4α isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3′ end splicing

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is essential for the establishment and maintenance of liver-specific gene expression. The HNF4 alpha gene codes for several isoforms whose developmental and physiological relevance has not yet been explored. HNF4 alpha1 and HNF4 alpha7 originate from different promoters, while alternative splicing in 3' leads to HNF4 alpha2 and HNF4 alpha8, respectively. HNF4 alpha7/alpha8 were abundantly expressed in embryonic liver and fetal-like hepatoma cells. HNF4 alpha1/alpha2 transcripts were up-regulated at birth and represented the only isoforms in adult-like hepatoma cells. In line with its expression profile, HNF4 alpha7 activated more avidly than HNF4a I 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 HNF4 alpha. The sequential expression of HNF4 alpha7/alpha8 and HNF4 alpha1/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. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.