Name
Abstract | ||
|---|---|---|
Pancreatic beta-cells are the target of an autoimmune attack in type 1 diabetes mellitus (T1DM). This is mediated in part by cytokines, such as interleukin (IL)-1beta and interferon (IFN)-gamma. These cytokines modify the expression of hundreds of genes, leading to beta-cell dysfunction and death by apoptosis. Several of these cytokine-induced genes are potentially regulated by the IL-1beta-activated transcription factor (TF) nuclear factor (NF)-kappaB, and previous studies by our group have shown that cytokine-induced NF-kappaB activation is pro-apoptotic in beta-cells. To identify NF-kappaB-regulated gene networks in beta-cells we presently used a discriminant analysis-based approach to predict NF-kappaB responding genes on the basis of putative regulatory elements.The performance of linear and quadratic discriminant analysis (LDA, QDA) in identifying NF-kappaB-responding genes was examined on a dataset of 240 positive and negative examples of NF-kappaB regulation, using stratified cross-validation with an internal leave-one-out cross-validation (LOOCV) loop for automated feature selection and noise reduction. LDA performed slightly better than QDA, achieving 61% sensitivity, 91% specificity and 87% positive predictive value, and allowing the identification of 231, 251 and 580 NF-kappaB putative target genes in insulin-producing INS-1E cells, primary rat beta-cells and human pancreatic islets, respectively. Predicted NF-kappaB targets had a significant enrichment in genes regulated by cytokines (IL-1beta or IL-1beta + IFN-gamma) and double stranded RNA (dsRNA), as compared to genes not regulated by these NF-kappaB-dependent stimuli. We increased the confidence of the predictions by selecting only evolutionary stable genes, i.e. genes with homologs predicted as NF-kappaB targets in rat, mouse, human and chimpanzee.The present in silico analysis allowed us to identify novel regulatory targets of NF-kappaB using a supervised classification method based on putative binding motifs. This provides new insights into the gene networks regulating cytokine-induced beta-cell dysfunction and death. |
Year | DOI | Venue |
|---|---|---|
2007 | 10.1186/1471-2105-8-55 | BMC Bioinformatics |
Keywords | Field | DocType |
gene expression profiling,activating transcription factor,signal transduction,feature selection,microarrays,algorithms,cross validation,gene regulation,bioinformatics,leave one out cross validation,quadratic discriminant analysis,noise reduction,nf kappa b,gene network,discriminant analysis,gene expression regulation | Interferon,NFKB1,Interleukin,Gene,Biology,Regulation of gene expression,Signal transduction,Bioinformatics,Genetics,Transcription factor,Gene expression profiling | Journal |
Volume | Issue | ISSN |
8 | 1 | 1471-2105 |
Citations | PageRank | References |
15 | 0.38 | 10 |
Authors | ||
3 | ||
Name | Order | Citations | PageRank |
|---|---|---|---|
| Najib Naamane | 1 | 16 | 0.76 |
| jacques van helden | 2 | 750 | 65.29 |
| Decio L Eizirik | 3 | 57 | 4.85 |