Species-specific differences in the expression of the HNF1A, HNF1B and HNF4A genes.
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.


RESULTS
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 (DeltaDeltaCt) 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
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.
Harries
Lorna W
LW
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, University of Exeter, Exeter, United Kingdom. L.W.Harries@exeter.ac.uk
Brown
James E
JE
Gloyn
Anna L
AL
D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000096:biosynthesis*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000096:biosynthesis*; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; C496496:Hnf1b protein, mouse; C068755:Hnf1b protein, rat; C496593:Hnf4a protein, mouse; C496594:Hnf4a protein, rat; D051539:Hepatocyte Nuclear Factor 1-beta