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Application of Comparative Transcriptional Genomics to Identify Molecular Targets for Pediatric IBD
Kai Fang1, Matthew B Grisham2, Christopher G Kevil3
1Division of Digestive Diseases, Inflammatory Bowel Disease Center, David Geffen School of Medicine at UCLA , Los Angeles, CA , USA.
Abstract:
Experimental models of colitis in mice have been used extensively for analyzing the molecular events that occur during inflammatory bowel disease (IBD) development. However, it is uncertain to what extent the experimental models reproduce features of human IBD. This is largely due to the lack of precise methods for direct and comprehensive comparison of mouse and human inflamed colon tissue at the molecular level. Here, we use global gene expression patterns of two sets of pediatric IBD and two mouse models of colitis to obtain a direct comparison of the genome signatures of mouse and human IBD. By comparing the two sets of pediatric IBD microarray data, we found 83 genes were differentially expressed in a similar manner between pediatric Crohn's disease and ulcerative colitis. Up-regulation of the chemokine (C-C motif) ligand 2 (CCL2) gene that maps to 17q12, a confirmed IBD susceptibility loci, indicates that our comparison study can reveal known genetic associations with IBD. In comparing pediatric IBD and experimental colitis microarray data, we found common signatures amongst them including: (1) up-regulation of CXCL9 and S100A8; (2) cytokine-cytokine receptor pathway dysregulation; and (3) over-represented IRF1 and IRF2 transcription binding sites in the promoter region of up-regulated genes, and HNF1A and Lhx3 binding sites were over-represented in the promoter region of the down-regulated genes. In summary, this study provides a comprehensive view of transcriptome changes between different pediatric IBD populations in comparison with different colitis models. These findings reveal several new molecular targets for further study in the regulation of colitis.
Insights
Comparing pediatric inflammatory bowel disease (IBD) with mouse colitis models reveals shared molecular signatures. This study identifies key gene expression patterns and regulatory elements, offering new targets for IBD research.
Area of Science:
- Genomics
- Molecular Biology
- Gastroenterology
Background:
- Experimental colitis models are crucial for studying inflammatory bowel disease (IBD) pathogenesis.
- Direct molecular comparisons between human IBD and mouse models are lacking, limiting translational research.
Purpose of the Study:
- To compare genome-wide gene expression patterns between pediatric IBD and experimental colitis models.
- To identify conserved molecular signatures and potential therapeutic targets for IBD.
Main Methods:
- Global gene expression profiling (microarray) of pediatric IBD patient samples and mouse colitis models.
- Comparative analysis of differentially expressed genes and promoter region transcription factor binding sites.
Main Results:
- Identified 83 differentially expressed genes common to pediatric Crohn's disease and ulcerative colitis.
- Found shared molecular signatures between pediatric IBD and mouse colitis, including CXCL9 and S100A8 up-regulation.
- Detected dysregulation in the cytokine-cytokine receptor pathway and identified over-represented transcription factor binding sites (IRF1, IRF2, HNF1A, Lhx3).
Conclusions:
- This study provides a comprehensive transcriptome comparison between human IBD and experimental colitis.
- Shared molecular pathways and gene signatures highlight conserved mechanisms in IBD development.
- Identified novel molecular targets for further investigation in IBD regulation.
