In silico identification of NF-kappaB-regulated genes in pancreatic beta-cells

Autor: Jacques van Helden, Decio L. Eizirik, Najib Naamane
Přispěvatelé: Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université libre de Bruxelles (ULB), European Project: SFRH/BPD/38218/2007,FCT::Pós-Doutoramento,SFRH/2007,SFRH/BPD/38218/2007(2008)
Jazyk: angličtina
Rok vydání: 2007
Předmět:
[SDV]Life Sciences [q-bio]
Gene regulatory network
Oligonucleotide Array Sequence Analysis -- methods
Biochemistry
Gene Expression Regulation -- physiology
Mice
Structural Biology
Insulin-Secreting Cells
Gene Expression Profiling -- methods
NF-kappa B -- metabolism
T1DM
NF-kappaB
lcsh:QH301-705.5
Oligonucleotide Array Sequence Analysis
Regulation of gene expression
Genetics
0303 health sciences
Applied Mathematics
030302 biochemistry & molecular biology
NF-kappa B
Discriminant Analysis
Sciences bio-médicales et agricoles
Computer Science Applications
Cytokines -- metabolism
Cytokines
lcsh:R858-859.7
DNA microarray
Algorithms
Signal Transduction
Research Article
Pan troglodytes
Cytokine gene signatures
In silico
Biology
lcsh:Computer applications to medicine. Medical informatics
Models
Biological
03 medical and health sciences
Animals
Humans
Signal Transduction -- physiology
Molecular Biology
Gene
Transcription factor
030304 developmental biology
Gene Expression Profiling
Pancreatic beta-cells
NFKB1
Rats
Gene expression profiling
Gene Expression Regulation
lcsh:Biology (General)
Insulin-Secreting Cells -- metabolism
[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Zdroj: BMC Bioinformatics
BMC Bioinformatics, BioMed Central, 2007, 8 (1), pp.55. ⟨10.1186/1471-2105-8-55⟩
BMC Bioinformatics, Vol 8, Iss 1, p 55 (2007)
BMC bioinformatics, 8
ISSN: 1471-2105
DOI: 10.1186/1471-2105-8-55⟩
Popis: BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.
Journal Article
Research Support, Non-U.S. Gov't
info:eu-repo/semantics/published
Databáze: OpenAIRE
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