- Article -
| In Silico Biology 9, 0028 (2009); ©2009, Bioinformation Systems e.V. |
In silico analysis of T-bet activity in peripheral blood mononuclear cells in patients with inflammatory bowel disease (IBD)
Nielsen Q. Fernandez-Becker1 and Alan C. Moss2*
1 School of Medicine, Stanford University, 300 Pasteur Drive, Stanford, CA 94305
2 Center for Inflammatory Bowel Disease, Division of Gastroenterology, Rose 1 / East, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215
* Corresponding author
Email: amoss@bidmc.harvard.edu
Edited by E. Wingender; received May 20, 2009; revised August 28; accepted September 06, 2009; published November 22, 2009
Abstract
T-bet (TBX21) is a transcription factor that regulates T-cell differentiation, and has recently been implicated in the pathogenesis of Crohn's disease (CD). The regulatory networks through which T-bet affects immune function are unknown.
An NCBI gene expression profile from patients with CD and controls was analyzed. T-bet transcription factor binding sites and promoter modules were identified using promoter analysis software. Functional correlations between T-bet-containing promoters were determined using data mining and ontological analysis.
T-bet expression in CD peripheral blood mononuclear cells (PBMCs) (n = 59) was significantly reduced compared to control (n = 42) (p < 0.0001) and ulcerative colitis PBMCs (n = 26), (p = 0.005). The promoter regions of all genes differentially-expressed in CD were probed for T-bet Transcription Factor Binding Sites (TFBSs). Twenty-three genes contained transcription-factor binding sites for T-bet; 8 were down-regulated, and 15 were up-regulated in CD-PBMCs. Three genes (S100A16, ABHD3 and EZH1) that were down-regulated in CD-PBMCs contained a complex promoter module consisting of T-bet and EGRF transcription-factor binding sites. Ontological analysis revealed that a significant number of differentially-expressed genes that contain T-bet binding sites are involved in innate immunity (8 genes, Z-score 4.11) and signal transduction (5 genes, Z-score 2.65).
This combination of gene expression datasets and promoter analysis has identified a network of genes that contain simple T-bet binding sites, and complex T-bet promoter modules, in their promoter regions. These results implicate a mechanism through which T-bet may influence innate immunity in CD.
Keywords: protein models, homology modelling, missense mutations, biological predictions, evaluation, quality of protein models, disease-causing mutations, structural explanations for mutations