Abstract
Background
Intestinal cells receive incoming signals from neighboring cells and microbial communities. Upstream signaling pathways transduce these signals to reach transcription factors (TFs) that regulate gene expression. In inflammatory bowel disease (IBD), most single nucleotide polymorphisms (SNPs) are in non-coding genomic regions containing TF binding sites. These SNPs can alter TF binding affinity, leading to regulatory shifts: TFs may lose or gain binding sites, causing a significant rewiring of the incoming signals regulating gene expression. Understanding this rewiring offers critical insights into the cellular mechanisms driving IBD pathogenesis.
Methods
To investigate this rewiring, we developed a systems genomics pipeline and analyzed individual genotype data from 2636 IBD patients to infer the incoming signals affecting patient-specific gene regulatory networks. Our in silico approach predicted changes in the repertoire of TFs binding to genomic loci due to IBD-associated non-coding SNPs in each patient compared to healthy controls. By functionally annotating the TFs in disease and healthy states, we highlighted the rewiring of upstream signaling pathways that may arise due to IBD-associated SNPs.
Results
We revealed that diverse non-coding SNP combinations in IBD patients lead to functional switches from healthy signals to disease-associated signals, capturing patient heterogeneity while uncovering common upstream regulators driving disease pathogenesis. Notably, rewired incoming signals belonged to key functional processes such as pro-inflammatory immune responses, epithelial barrier dysfunction, stress responses, wound healing, and antimicrobial defense pathways.
Conclusions
In summary, this work highlights the importance of personalized investigation of signaling processes upstream of genetic polymorphisms to gain a more comprehensive understanding of IBD pathogenesis
Intestinal cells receive incoming signals from neighboring cells and microbial communities. Upstream signaling pathways transduce these signals to reach transcription factors (TFs) that regulate gene expression. In inflammatory bowel disease (IBD), most single nucleotide polymorphisms (SNPs) are in non-coding genomic regions containing TF binding sites. These SNPs can alter TF binding affinity, leading to regulatory shifts: TFs may lose or gain binding sites, causing a significant rewiring of the incoming signals regulating gene expression. Understanding this rewiring offers critical insights into the cellular mechanisms driving IBD pathogenesis.
Methods
To investigate this rewiring, we developed a systems genomics pipeline and analyzed individual genotype data from 2636 IBD patients to infer the incoming signals affecting patient-specific gene regulatory networks. Our in silico approach predicted changes in the repertoire of TFs binding to genomic loci due to IBD-associated non-coding SNPs in each patient compared to healthy controls. By functionally annotating the TFs in disease and healthy states, we highlighted the rewiring of upstream signaling pathways that may arise due to IBD-associated SNPs.
Results
We revealed that diverse non-coding SNP combinations in IBD patients lead to functional switches from healthy signals to disease-associated signals, capturing patient heterogeneity while uncovering common upstream regulators driving disease pathogenesis. Notably, rewired incoming signals belonged to key functional processes such as pro-inflammatory immune responses, epithelial barrier dysfunction, stress responses, wound healing, and antimicrobial defense pathways.
Conclusions
In summary, this work highlights the importance of personalized investigation of signaling processes upstream of genetic polymorphisms to gain a more comprehensive understanding of IBD pathogenesis
| Original language | English |
|---|---|
| Pages (from-to) | 1-16 |
| Number of pages | 16 |
| Journal | Inflammatory Bowel Diseases |
| Early online date | 7 Sept 2025 |
| DOIs | |
| Publication status | E-pub ahead of print - 7 Sept 2025 |
Keywords
- Signalling pathways
- Gene regulatory networks
- Single nucleotide polymorphisms
- Systems genomics
- Inflammatory Bowel Disease
- Crohn's disease
- Ulcerative colitis