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Background  The  HNF1A ,  HNF1B  and  HNF4A  genes are part of an autoregulatory network in mammalian pancreas, liver, kidney and gut. The layout of this network appears to be similar in rodents and humans, but inactivation of  HNF1A ,  HNF1B  or  HNF4A  genes in animal models cause divergent phenotypes to those seen in man. We hypothesised that some differences may arise from variation in the expression profile of alternatively processed isoforms between species.    Methodology/Principal Findings  We measured the expression of the major isoforms of the  HNF1A ,  HNF1B  and  HNF4A  genes in human and rodent pancreas, islet, liver and kidney by isoform-specific quantitative real-time PCR and compared their expression by the comparative Ct (ΔΔCt) method. We found major changes in the expression profiles of the HNF genes between humans and rodents. The principal difference lies in the expression of the  HNF1A  gene, which exists as three isoforms in man, but as a single isoform only in rodents. More subtle changes were to the balance of  HNF1B  and  HNF4A  isoforms between species; the repressor isoform  HNF1B(C)  comprised only 6% in human islets compared with 24–26% in rodents (p = 0.006) whereas  HNF4A9  comprised 22% of  HNF4A  expression in human pancreas but only 11% in rodents (p = 0.001).    Conclusions/Significance  The differences we note in the isoform-specific expression of the human and rodent  HNF1A ,  HNF1B  and  HNF4A  genes may impact on the absolute activity of these genes, and therefore on the activity of the pancreatic transcription factor network as a whole. We conclude that alterations to expression of  HNF  isoforms may underlie some of the phenotypic variation caused by mutations in these genes.

Species-Specific Differences in the Expression of the HNF1A, HNF1B and HNF4A Genes