Leukocyte Recruitment Alters Pathological Angiogenesis Gene Expression During DSS Colitis

Abstract

Experimental models of colitis in mice have been extensively used to study molecular events that occur during inflammatory bowel disease (IBD) development. However, direct and comprehensive comparison of mouse and human inflamed colon tissue at the genome level remains largely unknown and to what extent such differences reflect changes associated with human IBD. Here we report comparative functional genomic analysis between experimental colitis models and pediatric IBD. Two sets of pediatric IBD microarray data (GEO accession number GSE9686 and GSE10616) and experimental colitis microarray data (DSS colitis model GEO number GSE22307 and T-cell transfer colitis model GEO number 27302) were used for comparative functional genome expression pattern analysis. All microarray data were obtained using Affymetrix GeneChip arrays providing the most comprehensive coverage of transcribed genomes of human or mouse. Microarray data were input into Genesifter software and normalized for comparison using the Robust Multichip Averaging (RMA) method. Threshold value for significant differences in gene expression was set at 2 fold and the Benjamini-Hochberg test used to diminish false discovery rates. Identified genes were uploaded into Ingenuity software for network analysis, and cREMaG (cis-Regulatory Elements in the Mammalian Genome) software for transcription factor/promoter analysis. Microarray analysis revealed that chitinase 3-like 1(cartilage glycoprotein-39, CHI3L1), Cysteine-rich, angiogenic inducer 61 (CYR61, or CCN1), and Chemokine (C-C motif) ligand 2 (CCL2) were up regulated in both pediatric CD and UC. Ingenuity network analysis of differentially expressed genes from pediatric CD was clustered into 8 networks and pediatric UC into 25 networks. By comparison of pediatric IBD and experimental colitis microarray data, we found the following common features: 1) CXCL9 and S100A8 were abundantly up regulated; 2) cytokine-cytokine receptor networks were dysregulated; and 3) IRF-1 transcription binding sites were over represented in the promoter region of up regulated genes, while HNF1A and Lhx3 binding sites were over represented in the promoter region of the down regulated genes. Together, our study provides a comprehensive comparative view of genome expression and transcription factor profile changes between pediatric IBD and experimental colitis models revealing common pathways that may be useful for future therapeutics.