Affiliations: School of Medicine, Stanford University, Stanford, CA,
USA | Center for Inflammatory Bowel Disease, Division of
Gastroenterology, Boston, MA, USA
Note: [] Corresponding author: Alan C. Moss, Center for Inflammatory
Bowel Disease, Division of Gastroenterology, Rose 1 / East, Beth Israel
Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. E-mail:
[email protected]
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
