Human Molecular Genetics, 2001, Vol. 10, No. 19 2089-2097
© 2001 Oxford University Press
A distant upstream promoter of the HNF-4
gene connects the transcription factors involved in maturity-onset diabetes of the young
Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany, 1Centre for Molecular Genetics, Institute of Clinical Science, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter EX2 5AX, UK and 2Division of General Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands
Received May 15, 2001; Revised and Accepted July 11, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant subtype of early-onset diabetes mellitus due to defective insulin secretion by the pancreatic ß-cell in humans. Five different genes have been identified including those encoding the tissue-specific transcription factors expressed in pancreatic ß-cells, i.e. HNF-4
(MODY1), HNF-1 (MODY3), IPF-1 (also known as PDX-1, MODY4) and HNF-1ß (MODY5). Analyzing the transcription of the HNF-4 gene, we now identify an alternative promoter, P2, which is 46 kb 5' to the previously identified P1 promoter of the human gene. Based on RT–PCR this distant upstream P2 promoter represents the major transcription site in pancreatic ß-cells, but is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter reveal functional binding sites for HNF-1, HNF-1ß and IPF-1, the other transcription factors known to encode MODY genes. We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4 gene co-segregates with diabetes (LOD score 3.25). These data suggest a regulatory network of the four MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF-4 gene. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by an autosomal dominant inheritance, an early onset usually before 25 years of age and an impaired glucose stimulated insulin secretion rate due to dysfunction of the pancreatic ß-cells (1–3). One of the five identified MODY genes represents glucokinase (MODY2) (4) whose defective function leads to an impaired sensing of the glucose level in the blood (5,6). The other four MODY genes are the transcription factors hepatocyte nuclear factor (HNF)-4
(MODY1) (7), HNF-1 (MODY3) (8), insulin promoter factor 1 (IPF-1/Pdx-1, MODY4) (9) and HNF-1ß (MODY5) (10). These four cell-specific transcription factors are known to be involved in the regulation of genes implicated in glucose metabolism and insulin secretion (11–13), but their precise role leading to MODY is still unclear. Clearly, the MODY4 transcription factor IPF-1 is essential for islet cell development and differentiation, as homozygous inactivation of the IPF-1 gene in mice and humans causes pancreas agenesis (14–16). In contrast, the transcription factors HNF-4, HNF-1 and HNF-1ß have been primarily associated with their function in hepatocytes whereas their function in ß-cell-specific gene control has been investigated only recently (reviewed in 17). More importantly, a connection of the three HNF proteins with IPF-1 has not been reported.
HNF-4 represents a cell-specific transcription factor that is expressed in liver, kidney, intestine, stomach and pancreas. It is an orphan member of the nuclear receptor superfamily, all of which contain a potential ligand binding domain, but a ligand has not been identified definitively (reviewed in 18–20). The mutations in the human HNF-4 gene leading to MODY1 are located within various domains of the protein and impair the function of the transcription factor to a varying degree (reviewed in 17). The clinical phenotypes of MODY1 and MODY3 patients who carry mutations in the transcription factors HNF-4 and HNF-1, respectively, show a similar progressive loss of ß-cell function and increase in hyperglycaemia with age (1). This may be due to the fact that both factors are part of the same network of transcription factors where it is proposed that HNF-4 acts upstream of HNF-1 (21–23). The observation that a naturally occurring mutation is located within the HNF-4 binding site of the HNF-1 gene promoter (24) supports the existence of such a hierarchical order. However, as the HNF-4 gene promoter contains an HNF-1 binding site (25,26), HNF-1 as well as HNF-1ß are possible regulators of HNF-4 expression, implying in addition a reciprocal regulatory loop. Apart from the HNF-1 binding site the HNF-4 promoter contains binding sites for HNF-3, HNF-6 and GATA 6 (19,27), factors that are present in hepatocytes as well as in pancreatic ß-cells.
Differential splicing of the HNF-4 gene suggests a complex expression pattern of HNF-4 (19); the original identified isoform is HNF-41 (28), and HNF-42 and 3, for example, are variants of the F domain containing a longer or shorter C-terminus, respectively (29–32) and the splice variant HNF-44 contains two additional exons (1B and 1C) in the N-terminal part of the protein (31,33). Recently, we identified an alternative 5' exon in the murine HNF-47 splice variant that is indicative for a differentially controlled second promoter (34).
In the present study we identified the human homolog of the murine splice variant HNF-47 (34) that is derived from the alternative promoter P2 46 kb 5' to the previously identified P1 promoter of the HNF-4 gene. As this distant upstream promoter is the major transcription start site in rat insulinoma INS-1 cells and contains functional binding sites for the other MODY transcription factors HNF-1, HNF-1ß and IPF-1, we propose that the four MODY transcription factors are part of a regulatory network interconnected at the distant upstream P2 promoter of the HNF-4 gene.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A distant upstream promoter of the HNF-4
geneThe different splice variants of the human HNF-4
gene (33) are schematically presented in Figure 1A. As we have previously identified the alternative transcript HNF-47 (named HNF-4P2 in the following) containing the novel exon P2 in the RNA of mouse tissues (34), we searched for the corresponding sequence in the human genome. Using the murine P2 exon as hybridization probe we identified the homologous sequence in a human P1-derived artificial chromosome (PAC) clone (PAC 114 E13) containing the HNF-4 gene (33). Sequencing revealed a 154 nucleotide sequence with 82% homology to the mouse P2 exon including the ATG translation initiation codon and a 5' splice donor site (Fig. 1B). This sequence is present in the human genomic data bank (NT_011403) and the 5' splice donor site is 45 529 nucleotides upstream of the P1 promoter start site of the human HNF-4 gene (Fig. 1A). To prove the existence of a human HNF-4 transcript containing the P2 exon linked to the exon 2 we performed RT–PCR on RNA of the human hepatoma cell line HepG2 and the human renal carcinoma cell line SK-RC9 using a forward primer from exon P2 and a reverse primer from exon 4. Sequencing the major PCR product identified a transcript containing exon P2 linked to exons 2, 3 and 4. This establishes that the distant upstream exon P2 is properly spliced to exon 2 of the HNF-4 gene in HepG2 and SK-RC9 cells and generates an open reading frame with 16 alternative N-terminal amino acids previously identified in the murine cDNA (34). A minor PCR product represented a transcript where exon P2 was linked to exon 4. The significance of this low abundant transcript that lacks the open reading frame for the DNA binding domain has not been further investigated.
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The splice variant HNF-4
P2 is the predominant transcript in pancreatic ß-cellsTo explore the significance of the HNF-4
P2 splice variant in ß-cells of the pancreas we analyzed cell lines of the rat as corresponding cells from humans were not available. Using RT–PCR and appropriate primers we could show that the HNF-4P2 splice variant is transcribed in the rat insulinoma cell line INS-1 and to a lower level in the hepatoma cell line FT0-2B, whereas the splice variants HNF-4P1 derived from the previously identified promoter P1 are exclusively expressed in the cell line of hepatic origin (Fig. 2). This result suggests that in ß-cells of the pancreas HNF-4 expression is mainly initiated at the P2 promoter.
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The alternative promoter P2 is active in pancreatic ß-cells and hepatic cells and contains a functional HNF-1 binding site
To assess the function of the P2 promoter of the HNF-4
gene we fused the P2 promoter sequence, extending from –2200 to the translation initiation site –1, to the luciferase gene and used this P2/–2200 reporter construct in transfection assays. As shown in Figure 3 high promoter activity was seen in transfection experiments using INS-1 cells. This activity remained high in various 5' deletion constructs up to the position –198 bp upstream of the ATG codon, but was completely lost upon a further deletion to –164. Using the P2/–2200 construct in the hepatoma cell line FT0-2B, 
3-fold lower activity was seen compared with the activity found in INS-1 cells (Fig. 3). Analyzing the various deletion constructs in the hepatoma cells we identified a 3-fold drop in activity between –2200 and –285 and a complete loss of activity between –198 and –164. Comparing these data with the transfections in INS-1 cells, we conclude that there is a minor regulatory element between –2200 and –285 that is restricted in its activity to hepatoma cells, and a major regulatory element between –198 to –164 that is functional in both cell types. Searching for binding sites in this region revealed at –181 a potential binding site for the transcription factors HNF-1 and HNF-1ß (Fig. 1B) known to be expressed in hepatocytes and pancreatic ß-cells (18). To test whether HNF-1 transcription factors play a role in the activation of the alternative promoter of HNF-4 we introduced a single nucleotide exchange (35) into the HNF-1 binding site of the P2/–285 reporter construct. The resulting construct P2/–285HBmut was tested in transfected INS-1 as well as FT0-2B cells in comparison with the wild-type sequence. Figure 3 shows that a mutated HNF-1 binding site results in a markedly decreased transactivation in both INS-1 and FT0-2B cells, indicating that HNF-1 and HNF-1ß are major regulators of the HNF-4 P2 promoter.
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A T
C polymorphism within the alternative promoter P2 co-segregates with MODY1Based on our data given in Figure 2 the P2 promoter is the major transcription start site of the HNF-4
gene in ß-cells of the pancreas and we therefore wondered whether it is mutated in MODY1 patients, in whom mutations were excluded by direct sequencing of the coding sequence, splice sites and minimal promoter of the five known MODY genes (36). Sequencing this distant upstream HNF-4 gene sequence of seven probands, we identified one patient with a heterozygous nucleotide substitution of C for T at position –146 (Fig. 1B). In addition to the initial sequencing we re-sequenced the whole coding sequence of the HNF-4 gene in both directions; splice sites and the P1 promoter in the proband and all these sequences were normal. The TC variant at position –146 was not detected in 50 control subjects, suggesting that it was a possible etiological MODY1 mutation. Extended family studies supported this: the heterozygous –146 TC substitution was present in all 10 diabetic family members and absent in the six non-diabetic family members (Fig. 4). Using previously defined MODY parameters (37) the LOD score was significant at 3.25, supporting the idea that the TC substitution at –146 was a MODY1 associated mutation.
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The MODY1 associated mutation impairs the promoter activity in INS-1 cells
To investigate whether the –146T
C mutation within the alternative promoter P2 functionally affects promoter activation we introduced this mutation into the reporter gene construct P2/–285, resulting in the construct P2/–285TC. Comparing the activity of the P2/–285 wild-type construct with the performance of the P2/–285TC mutant, we observed a 3-fold lower activity in INS-1 cells for the mutant construct. This decreased activity of the construct containing the MODY1 associated mutation was specific for the ß-cells as the wild-type and the mutant constructs had identical activity in the FT0-2B hepatoma cells (Fig. 5). These data imply that the variant affects promoter activity cell specifically.
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The MODY1 associated mutation –146T
C interferes with the function of the transcription factors CDX-2 and IPF-1As reporter gene activity of P2/–285T
C is exclusively impaired in the insulinoma cell line INS-1 in comparison with the wild-type P2/–285 (Fig. 5), we suspected that some ß-cell-specific transcription factors interact with the –146TC site. Although the sequence containing the –146TC site contains the core element ATTA of the binding sites of homeobox proteins (38), this is not sufficient to identify the transcription factor affected by the –146TC mutation. Therefore, we cotransfected the P2 promoter constructs with expression vectors encoding various cell-specific transcription factors into Hela cells that lack ß-cell-specific transcription factors. As shown in Figure 6A, cell-specific transcription factors increased the activity of the P2/–285 reporter construct to a varying degree ranging from 2- to 11-fold. HNF-6 had the greatest effect on P2 promoter activity and this was more than twice the effect of IPF-1 or HNF-1ß and >5-fold the effect of the other transcription factors tested. To identify factors that are affected by the –146TC mutation we compared the transactivation potential of a given transcription factor on the wild-type (P2/–285) and the mutated (P2/–285TC) reporter gene construct (Fig. 6B). The results shown in Figure 6B indicate that the activities of the factors CDX-2 and IPF-1 are significantly reduced by the mutated P2/–285TC reporter gene construct in comparison with the wild-type P2/–285 construct, whereas all other factors used show similar transactivation potentials on both reporter gene constructs. The significance for the reduced activity on the construct P2/–285TC for GATA6 and even HNF-1 is low using 150 ng of expression vector and cannot be confirmed in experiments using an input of 300 ng of expression vector (data not shown). Thus, the ß-cell-specific transcription factors CDX-2 and IPF-1, both of which are homeodomain proteins, are good candidates for regulating the alternative HNF-4 promoter via a sequence element spanning position –146 where we could identify a MODY1 associated mutation.
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IPF-1 binding to DNA is affected by the MODY1 associated mutation
To get independent evidence that CDX-2 and IPF-1 are involved in ß-cell-specific regulation of the alternative HNF-4
promoter P2, we performed gel shift experiments with in vitro synthesized proteins and an oligonucleotide comprising the region –161 to –123 of the promoter P2 spanning nucleotide –146, where we found the MODY1 associated mutation TC. The quality of the translational products was controlled by synthesizing 35S-labeled proteins which were readily identified as proteins of the expected molecular weight on an SDS polyacrylamide gel (data not shown). In gel shift experiments the recombinant CDX-2 protein did not bind to the –163 to –123 oligonucleotide (data not shown), whereas it bound to an oligonucleotide containing the Far-FLAT element of the rat insulin I gene (data not shown) as described by German et al. (39). Thus, we exclude CDX-2 as the binding protein of the sequence associated with the MODY mutation. In contrast, IPF-1 binds to the P2–161/–123 oligonucleotide forming a complex as marked in Figure 7A. The addition of increasing amounts of unlabeled wild-type oligonucleotide results in competition for the labeled complex. Increasing amounts of unlabeled mutant oligonucleotide containing the MODY1 associated mutation compete for the labeled complex as well but to a lesser extent, indicating that IPF-1 binds to the mutated oligonucleotide with reduced affinity in comparison with the wild-type sequence. This result was confirmed by corresponding competition experiments using an oligonucleotide containing the IPF-1 binding site of the Far-FLAT element of the rat insulin I gene (40,41) as labeled DNA and wild-type or mutant P2–161/–123 DNA as competitor (Fig. 7B). Sequence comparison of known IPF-1 binding sites of the human insulin gene and the human glucokinase gene (42) with the IPF-1 binding site within the human alternative P2 promoter shows high homology (Fig. 7C) and the TC substitution at –146 is predicted to decrease this homology by destroying the ATTA sequence that is the core element of binding sites of homeobox proteins (38).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the present study we have identified the distant upstream P2 promoter of the human HNF-4
(MODY1) gene which is homologous to the mouse cDNA fragment found previously as an alternative 5' exon (34). The homology region of 154 nucleotides includes the ATG translation initiation codon and the 5' splice donor site. In the human genome the P2 promoter is located 45 529 kb upstream of the so far known P1 promoter of the HNF-4 gene. It is most likely that the P2 promoter is localized in murine cells at such a far upstream position, too, as we failed to detect the corresponding sequence in the 10 kb flanking sequences of the cloned murine P1 promoter (25,43). Using RT–PCR we have proven that correct splicing occurs over these 46 kb in human cells of hepatic and renal origin leading to a transcript containing exon P2 linked to exon 2 of the HNF-4 gene. More importantly, we have shown that the P2 promoter is the exclusive transcription start site found in the rat insulinoma cell line INS-1, a well established model for pancreatic ß-cell function (44). In contrast the expression of the HNF-4 gene in the hepatoma cell line FT0-2B mainly initiates at the P1 promoter. This latter observation is confirmed by our previous analysis in the mouse where the transcripts driven by the P1 promoter predominate in the liver (34). However, we already noted in these experiments a differential use of the alternative P2 promoter depending on the cell type used. Most significantly, we observed an exclusive use of the P2 promoter in undifferentiated embryonic cells that, based on our new data, is apparently maintained in ß-cells of the pancreas (Fig. 2).
We speculate on the one hand that the dual promoter system of the HNF-4 gene may be important for the expression of slightly different transcription factors. This interpretation is supported by our previous finding that the transcription factor encoded by the P2 promoter transcript has a lower transactivation potential in transfection assays using HNF-4-dependent reporter genes (34). An alternative interpretation might be that the presence of two promoters allows a more complex regulation of the HNF-4 gene than with a single promoter. This assumption is supported by our analysis in this report, as we document a cell-specific use of the two promoters by establishing a regulation of the P2 promoter that is distinct from that of the P1 promoter. Reporter gene experiments reveal that the P2 promoter of HNF-4 contains functional binding sites for the three other transcription factors in which mutations cause MODY, i.e. HNF-1 (MODY3), HNF-1ß (MODY5) and IPF-1 (MODY4). These data imply a regulatory network connecting all four MODY transcription factors via the P2 promoter of the HNF-4 gene. The relevance of this regulatory network in man is supported by the MODY1 family with a mutated IPF-1 (MODY4) binding site in the P2 promoter in which the mutation strictly co-segregates with diabetes (Fig. 4). Taken together, these data support most convincingly that the MODY associated mutation in the HNF-4 P2 promoter is responsible for the disease observed in the human patients.
The evidence that the mutation found in the MODY1 family affects an IPF-1 binding site is supported by three findings. First, we have shown that the mutated site only affects the activity in the pancreatic ß-cells and not in hepatic cells (Fig. 5). A transcription factor such as IPF-1 is a good candidate, as it is present in ß-cells but not in hepatocytes. Secondly, the IPF-1-mediated transactivation of the P2 promoter in transfection assays is significantly reduced with the mutant promoter compared with the wild-type promoter (Fig. 6B). Thirdly, in gel retardation assays the binding of IPF-1 is impaired by the MODY associated mutation of the P2 promoter (Fig. 7A and B). In contrast, we exclude CDX-2 as a transcription factor interacting with the mutated site, as no binding could be shown in gel retardation assays. The fact that transactivation by CDX-2 is also reduced by the mutated site we consider as a consequence of the interplay of various tissue-specific transcription factors in the transfection assays.
In several studies it has been established that type 2 diabetes is linked to the chromosome region 20q12–q13.1 (45–47) which includes the HNF-4 gene. However, investigations failed to show any alteration in the P1 promoter and the exon region of the HNF-4 gene (48,49). Our finding of an alternative exon P2 46 kb 5' to the P1 promoter may justify a reinvestigation of this issue to include this far upstream region of the HNF-4 gene. We postulate that this extended 5' end of the HNF-4 transcription unit may serve as a large target for transcriptional interference and could possibly explain the linkage of type 2 diabetes to this genomic region.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Sequencing of the P2 alternative promoter of the HNF-4
gene in MODY subjectsSeven MODY probands were studied as they met clinical criteria for MODY (1) (autosomal dominant inheritance of non-insulin-dependent diabetes with at least two family members diagnosed before 25 years) but the five known MODY genes had been excluded by either direct sequencing and/or linkage (36). The alternative exon P2 was amplified by PCR using genomic DNA and primers: forward, 5'-TTC TGC TCC GGC CCT GTC-3'; and reverse, 5'-AAG CTG ACC GCA GTC CCG-3'. PCR was performed in a 25 µl volume containing, in addition to the standard reagents, 1 M betaine, 5% DMSO, 50 µM deaza GTP and 0.5 U AmpliTaq Gold (Applied Biosystems, UK). PCR cycling conditions were denaturation at 95°C for 12 min followed by 40 cycles of denaturation at 95°C for 1 min, annealing at 55°C for 1 min and extension at 72°C for 2 min, with a final 10 min extension at 72°C. PCR products were purified using the QIAquick PCR purification kit (Qiagen, UK) before both strands were sequenced using an ABI Prism BigDyeTM Terminator Cycle Sequencing Kit and an ABI 377 DNA sequencer (Applied Biosystems). After the mutation was detected all consenting family members of this Dutch caucasian MODY family were contacted and blood samples were taken for DNA extraction and subsequent direct sequencing for the mutation. Subjects not known to be diabetic were tested by measurement of HbA1c and fasting blood glucose. Subjects were only classifed as unaffected if both fasting plasma glucose and HbA1c were normal. Diabetes was diagnosed using the WHO criteria (50). There were no subjects in this pedigree with either impaired glucose tolerance or fasting hyperglycaemia. We assessed the significance of variants co-segregating with MODY using a previously described parametric LOD score analysis with age-related penetrances (37) and the MLINK (5.1) program.
Plasmid constructions
The expression vectors encoding human HNF-1 and human HNF-42 were generated as described previously (31,51). The expression vectors for mHNF-6 and rHNF-3ß (52) were generous gifts from Robert H. Costa (University of Illinois at Chicago), that for haCDX-2 (53) was from Cathy Mitchelmore (University of Copenhagen), that for hIPF-1 (54) was from Michael D. Walker (Weizmann Institute of Science) and that for mGATA6 (55) was from Edward E. Morrisey (University of Pennsylvania Health System). Luciferase reporter gene constructs were generated by introducing PCR fragments containing the appropriate HNF-4 P2 promoter sequence into the XhoI and HindIII restriction sites of the vector pGL3-BasicII (Promega). PCR was performed with a different set of forward primers corresponding to the 5'-end of the indicated promoter sequence and the reverse primer 5'-CCCAAGCTTGGGCCAAGCCCACCCAGC-3', introducing XhoI and HindIII restriction sites, respectively.
Cell lines, transfections and reporter gene assays
INS-1 cells (44) were cultured at 37°C in RPMI-1640 supplemented with penicillin (100 U/ml), streptomycin (100 U/ml), 10% heat inactivated fetal calf serum (Seromed), 1 mM sodium pyruvate, 10 mM HEPES and 50 µM mercaptoethanol. FT0-2B and HeLa cells were cultured at 37°C in DMEM supplemented with penicillin (100 U/ml), streptomycin (100 U/ml) and 10% heat inactivated fetal calf serum. Transfections of INS-1 and FT0-2B cells were performed using 0.5 µg of the HNF-4 P2-dependent luciferase reporter gene constructs per 3.3 cm cell culture dish together with 1.1 µg of pBluescriptKS+ and 6 µl of lipofectamine (Gibco BRL). HeLa cells were transfected using 1.3 µg reporter gene, 0.15 µg expression vector and 6 µl lipofectamine in a 3.3 cm cell culture dish. The final DNA concentration was equalized by the addition of pBluescriptKS+ vector.
RT–PCR
For RT–PCR total RNA was isolated from INS-1 and FT0-2B cells using the RNeasy Mini Kit (Qiagen). Reverse transcription and subsequent PCR were performed as described previously (34).
In vitro translation and gel shift experiments
CDX-2 and IPF-1 proteins were synthesized using the TNT T7 coupled reticulocyte lysate system (Promega). Gel shift experiments were performed as described previously (56) in a reaction mixture containing 30 ng of salmon sperm DNA, 10 mM HEPES (pH 7.9), 60 mM KCl, 1 mM EDTA, 1 mM dithiothreitol, 4% Ficoll 400, 0.4 µl of the in vitro translated proteins and 104 c.p.m. of 32P-labeled P2–161/–123 (5'-AGCTCCCACCTTGGGTGATTAGAAGAATCAATAAGATAACCGG-3'/5'-GATCCCGGTTATCTTATTGATTCTTCTAATCACCCAAGGTGGG-3') or Far-FLAT (5'-AGCTGATCCTTCATCAGGCCATCTGGCCCCTTGTTAATAATCTAATTACCCTAGGTCTA-3'/5'-GATCTAGACCTAGGGTAATTAGATTATTAACAAGGGGCCAGATGGCCTGATGAAGGATC-3') oligonucleotide.
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ACKNOWLEDGEMENTS |
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We thank Robert H. Costa, Cathy Mitchelmore, Michael D. Walker and Edward E. Morrisey for providing the expression vectors for mHNF-6/rHNF3-ß, haCDX-2, hIPF-1 and mGATA6, respectively, and Diane Jarvis for the DNA extraction. This work was supported by the Deutsche Forschungsgemeinschaft (Ry 5/4-2 and Th 799/1-1) and Diabetes UK. T.M.F. is a Career Scientist supported by the South and West National Health Service Research Directorate and C.J.T. has a fellowship of the Dutch Diabetes Foundation.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +49 201 723 3111; Fax: +49 201 723 5905; Email: gerhart.ryffel@uni-essen.de
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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