Patient-specific regulatory network rewiring in inflammatory bowel disease: how genetic polymorphisms divert incoming signals and contribute to disease pathogenesis
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2025-10-01
Date Acceptance
2025-09-01
Citation
Inflammatory Bowel Diseases, 2025, 31 (10), pp.2665-2680
ISSN
1078-0998
Publisher
Oxford University Press
Start Page
2665
End Page
2680
Journal / Book Title
Inflammatory Bowel Diseases
Volume
31
Issue
10
Copyright Statement
© The Author(s) 2025. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40914875
PII: 8248830
Subjects
ACTIVATION
AUTOIMMUNITY
Crohn's disease
DATABASE
Gastroenterology & Hepatology
Gene regulatory networks
GFI1
Inflammatory Bowel Disease
INNATE
INTESTINAL INFLAMMATION
Life Sciences & Biomedicine
RECEPTOR
Science & Technology
Signalling pathways
Single nucleotide polymorphisms
SINGLE NUCLEOTIDE POLYMORPHISMS
Systems genomics
T-BET
TRANSCRIPTION FACTOR-BINDING
Ulcerative colitis
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2025-09-07