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. 2009 Nov 16;4(11):e7855.
doi: 10.1371/journal.pone.0007855.

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

Lorna W Harries  1 , James E Brown, Anna L Gloyn
Affiliations

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

Lorna W Harries et al. PLoS One. .

Abstract

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 (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/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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Alternatively processed forms of the HNF1A, HNF1B and HNF4A genes.
The structure of alternately processed isoforms of the HNF1A (1a), HNF1B (1b) and HNF4A (1c) genes is given. Exons are indicated in gray and numbered, and isoform-specific novel coding regions in black. The position of the isoform-specific probes are given by black bars.
Figure 2
Figure 2. The expression profile of the HNF1A gene in human, mouse and rat.
The expression profile of the HNF1A gene in human, mouse and rat is given. The species is given on the X-axis and the relative quantification of each isoform relative to the B2M gene is given on the Y-axis. Each transcript is normalized to the levels of human HNF1A(A) in each tissue. HNF1A(A) is given by black bars, HNF1A(B) by grey bars and HNF1A(C) by white bars. Error bars indicate the upper and lower limits of transcript expression. a. islet, b. pancreas, c. liver, d. kidney.
Figure 3
Figure 3. The expression profile of the HNF1B gene in human, mouse and rat.
The expression profile of the HNF1B gene in human, mouse and rat is given. The species and transcript identity identity is given on the X-axis and the relative quantification of each isoform relative to the B2M gene is given on the Y-axis. Each transcript is normalized to the levels of human HNF1A(A) in each tissue. Error bars indicate the upper and lower limits of transcript expression. a. islet, b. pancreas, c. liver, d. kidney.
Figure 4
Figure 4. The expression profile of the HNF4A gene in human, mouse and rat.
The expression profile of the HNF4A gene in human, mouse and rat is given. The species and transcript identity is given on the X-axis and the relative quantification of each isoform relative to the B2M gene is given on the Y-axis. Each transcript is normalized to the levels of human HNF1A(A) in each tissue. Error bars indicate the upper and lower limits of transcript expression. a. islet, b. pancreas, c. liver, d. kidney.
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