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Transcriptional Profiling of Type 1 Diabetes Genes on Chromosome 21 in a Rat Beta-Cell Line and Human Pancreatic Islets

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Transcriptional Profiling of Type 1 Diabetes Genes on Chromosome 21 in a Rat Beta-Cell Line and Human Pancreatic Islets Genes and Immunity (2007) 8, 232–238 & 2007 Nature Publishing Group All rights reserved 1466-4879/07 $30.00 www.nature.com/gene ORIGINAL ARTICLE Transcriptional profiling of type 1 diabetes genes on chromosome 21 in a rat beta-cell line and human pancreatic islets R Bergholdt1, AE Karlsen1,2, PH Hagedorn3, M Aalund4, JH Nielsen5, M Kruhøffer6, T Ørntoft6, H Wang7, CB Wollheim7, J Nerup1,2 and F Pociot1,2 1Steno Diabetes Center, Gentofte, Denmark; 2Institute for Clinical Science, University of Lund, Lund, Sweden; 3Biosystems Department, Risø National Laboratory, Technical University of Denmark, Roskilde, Denmark; 4Neurotech A/S, Copenhagen, Denmark; 5Department of Medical Biochemistry and Genetics, University of Copenhagen, Copenhagen, Denmark; 6Molecular Diagnostic Laboratory, Aarhus University Hospital, Skejby, Aarhus, Denmark and 7Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland We recently finemapped a type 1 diabetes (T1D)-linked region on chromosome 21, indicating that one or more T1D-linked genes exist in this region with 33 annotated genes. In the current study, we have taken a novel approach using transcriptional profiling in predicting and prioritizing the most likely candidate genes influencing beta-cell function in this region. Two array- based approaches were used, a rat insulinoma cell line (INS-1ab) overexpressing pancreatic duodenum homeobox 1 (pdx-1) and treated with interleukin 1b (IL-1b) as well as human pancreatic islets stimulated with a mixture of cytokines. Several candidate genes with likely functional significance in T1D were identified. Genes showing differential expression in the two approaches were highly similar, supporting the role of these specific gene products in cytokine-induced beta-cell damage. These were genes involved in cytokine signaling, oxidative phosphorylation, defense responses and apoptosis. The analyses, furthermore, revealed several transcription factor binding sites shared by the differentially expressed genes and by genes demonstrating highly similar expression profiles with these genes. Comparable findings in the rat beta-cell line and human islets support the validity of the methods used and support this as a valuable approach for gene mapping and identification of genes with potential functional significance in T1D, within a region of linkage. Genes and Immunity (2007) 8, 232–238. doi:10.1038/sj.gene.6364379; published online 1 March 2007 Keywords: transcriptional profiling; type 1 diabetes; human islets; gene expression; chromosome 21; candidate gene Introduction genes for further analysis. In the present study, we have used transcriptional profiling in selecting the most likely Identification of susceptibility genes in complex genetic candidate genes based on functional significance. T1D diseases is a major challenge. In the process of identify- (MIM 222100) is a complex genetic disease of unknown ing disease-associated genes, classically two strategies etiology. In a previous T1D genome scan,1 a region on have been used, the functional candidate gene approach chromosome 21 showed some evidence of linkage to and the positional approach. The functional candidate T1D, especially in the Danish population (LOD 2.33, gene approach takes advantage of existing knowledge P ¼ 0.009). We have recently finemapped this region, also about the disease and genes are selected based on this in the Danish population, to a 6.3 Mb interval with a peak knowledge. This approach has been extensively used, NPL score of 3.61 (P ¼ 0.0002).2 Thirty-three known although, with varying success in type 1 diabetes (T1D). genes were identified in this region (www.ncbi.nlm.nih. With the positional approach, linkage analysis is used to gov), and all known single-nucleotide polymorphisms determine location of disease-linked regions. The (SNPs) in coding regions of these genes (dbSNP, http:// gene(s), thus identified, are subsequently further exam- www.ncbi.nlm.nih.gov/SNP/index.html, build 116) ined and their functional significance is evaluated. were examined. Globally, none of the SNPs showed Linkage peaks typically cover megabase (Mb)-wide association to T1D.2 However, subsets of data (e.g. regions, but workload, data management and costs for families responsible for the linkage signal) demonstrated finemapping can be significantly reduced by prioritizing T1D association of four genes: TTC3, OLIG2, KCNE1 and CBR1. From a statistical point, all 33 genes, positioned underneath the linkage peak, are equally good candidate Correspondence: Professor F Pociot, Steno Diabetes Center, Niels genes. Consequently, they should all be extensively Steensensvej 2, DK-2820 Gentofte, Denmark. E-mail: [email protected] studied. Expression levels of the genes, may, however, Received 13 November 2006; revised 21 January 2007; accepted 22 act as intermediate phenotypes between genomic DNA January 2007; published online 1 March 2007 sequence variations and more complex disease pheno- Transcriptional profiling of T1D genes on Chr. 21 R Bergholdt et al 233 types;3 and variation in gene expression has been shown critical region protein 1, Calcipressin-1) and CRYZL1 in large part as an outcome of polymorphisms in DNA (quinine oxidoreductase-like 1) genes were downregu- sequence.3,4 We have, therefore, taken a novel approach lated when comparing pdx-1-overexpressing cells stimu- for gene mapping, which uses transcriptional profiling as lated with IL-1b vs unstimulated pdx-1-overexpressing a method to select candidate genes within a region, that cells (Figure 1 and Table 1). In contrast, the ATP5O (ATP- is, prioritizing the genes of interest for further investiga- synthase O subunit) and IFNGR2 (interferon-gamma tion. In the present study, we have used model systems receptor beta chain precursor) genes were upregulated in primarily addressing beta-cell function and response. the presence of IL-1b (Figure 1 and Table 1). Additionally, Gene expression was evaluated by means of two array- the IFNAR1 (interferon-alpha/beta receptor alpha- based approaches. The first approach was based on a rat chain precursor) (P ¼ 0.01), DSCR5 (phosphatidylinositol insulinoma cell line (INS-1ab) overexpressing pancreatic N-acetylglucosaminyltransferase subunit P, PIGP) duodenum homeobox 1 (pdx-1).5,6 Beta-cell maturation is (P ¼ 0.03), TIAM1 (T-lymphoma invasion and metasta- dependent on sequential activation of different transcrip- sis-inducing protein 1) (P ¼ 0.01) and OLIG1 (oligoden- tion factors, including pdx-1,5 and is accompanied by drocyte transcription-factor 1) (P ¼ 0.001) genes were all increased sensitivity to the toxic effects of interleukin 1b upregulated by pdx-1 overexpression at 2 h and/or 24 h, (IL-1b).7 Cytokines have been shown to play a key role in as compared with the control situation without pdx-1 the destruction of beta cells,8 and we have demonstrated overexpression, independently of IL-1b stimulation. The an increased sensitivity to IL-1b in INS-1ab overexpres- CHAF1B (chromatin assembly factor 1 subunit-B) gene sing pdx-1.6 Extensive microarray analysis was carried was downregulated (P ¼ 0.003) by pdx-1 overexpression, out with these cells treated with IL-1b for different Table 1. periods of time. In the second approach, human Second, human pancreatic islet preparations from pancreatic islets from eight donors were examined in eight donors were examined in a separate array-based another array-based evaluation of gene expression of the evaluation of gene expression of all 33 positional human 33 positional human candidate genes with and without candidate genes with and without stimulation with a stimulation with a mixture of cytokines, mimicking the mixture of cytokines. Several of the chromosome 21 presumed pathogenesis of T1D in humans. candidate genes demonstrated expression levels that were downregulated in human islets following cytokine exposure, that is, ITSN1 (intersectin-1), TTC3 (tetratrico- peptide repeat protein-3), CHAF1B, HUNK (hormonally Results upregulated neu tumor-associated kinase), OLIG1 and Gene expression was evaluated by means of two CBR1 (carbonyl reductase 1) (Figure 2 and Table 1). Of different array-based approaches focusing on beta-cell these, HUNK and ITSN1 did not have a homologous function. Expression was evaluated in a rat beta-cell line gene in the rat and TTC3 was not on the rat Affymetrix overexpressing pdx-1, exposed to IL-1 for 2 and 24 h. Of chip. Genes demonstrated to be differentially expressed the 33 human genes, 27 have homologues in the rat. in both approaches were CHAF1B, OLIG1 and CBR1/ Twenty of these were represented by one or more probe CBR3. sets on the Affymetrix rat chip used, and were subjected Common expression patterns of genes may reflect to analysis in this rat beta-cell system. Of these, the CBR3 shared regulatory mechanisms. Promoter regions of the (carbonyl reductase 3), DSCR1 (Down’s syndrome selected genes were, therefore, compared for common Figure 1 Expression levels in rat genes (corresponding to human chromosome 21 genes), which are differentially expressed after IL-1b stimulation. Expression levels are expressed relative to unstimulated condition, and are provided for 2 and 24 h of IL-1b stimulation. *Comparisons with P-values o0.05. The CBR3 (P ¼ 0.04), DSCR1 (P ¼ 0.001) and CRYZL1 (P ¼ 0.03) genes were downregulated after IL-1b stimulation, whereas the IFNGR2 (P ¼ 1.4 Â 10À7) and ATP5O (P ¼ 0.006) genes were upregulated in the presence of IL-1b. Findings observed in this model system of course need confirmation
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