Bioinformatics Reveals Shared Genetic Pathways Linking Ulcerative Colitis and Bile Disease

A computational investigation has uncovered shared genetic variants, altered transcriptomes, and coordinated post-transcriptional pathways linking ulcerative colitis with primary sclerosing cholangitis. Ulcerative colitis represents a widespread inflammatory bowel disease characterized by persistent, relapsing mucosal inflammation across the gastrointestinal tract that causes substantial morbidity. Clinical records indicate that inflammatory bowel disease frequently involves extraintestinal organs, with extraintestinal manifestations arising in up to fifty percent of affected patients and occurring prior to gastrointestinal symptoms in roughly twenty-four percent of cases. Among these systemic complications, primary sclerosing cholangitis is an aggressive cholestatic disorder marked by biliary tree inflammation, progressive ductal fibrosis, strictures, liver cirrhosis, hepatic failure, and increased risk of cholangiocarcinoma. Primary sclerosing cholangitis develops in two to eight percent of patients diagnosed with ulcerative colitis, whereas ulcerative colitis occurs in approximately seventy to seventy-five percent of individuals with primary sclerosing cholangitis, pointing to shared pathogenic mechanisms that have remained largely unresolved at the molecular level.

To clarify these shared mechanisms, investigators established an integrated bioinformatics strategy evaluating publicly available genomic and transcriptomic datasets. The team queried the DisGeNET platform, extracting disorder-associated variants with a cut-off score greater than 0.5 using the disgenet2r package while filtering out entries lacking verified gene nomenclature. Simultaneously, the researchers screened the Gene Expression Omnibus database for human blood microarray datasets involving ulcerative colitis, primary sclerosing cholangitis, and healthy controls, requiring cohorts of at least ten samples. Two datasets satisfied these criteria: GSE119600, generated using the Illumina HumanHT-12 V4.0 platform and comprising forty-five primary sclerosing cholangitis, ninety-three ulcerative colitis, and forty-seven healthy blood samples, and GSE94648, processed on the Affymetrix Human Genome U133 Plus 2.0 array with twenty-five colitis and twenty-two healthy samples. Affymetrix data were normalized via Robust Multi-array Average in R version 4.4.2 using the Affy package, and differential expression analysis was performed with limma applying absolute log2 fold change of at least one and adjusted P-value below 0.05.

Analysis of DisGeNET records revealed marked inherited genetic overlap between both diseases. Investigators cataloged 1533 genes associated with ulcerative colitis and 452 linked to primary sclerosing cholangitis, uncovering 291 common genes. Polymorphism screening identified 325 single-nucleotide polymorphisms across 243 genes in colitis and 311 polymorphisms across 178 genes in cholangitis, with 132 single-nucleotide polymorphisms and their corresponding genes directly shared between both conditions. Notable shared variants highlighted by the authors included rs10889676 within IL23R, rs11230563 within CD6, rs11614178 within IFNG-AS1, rs12075255 within IL19, rs12987977 within IL18R1, rs1883832 within CD40, rs183686347, and rs2104286 within IL2RA. These shared loci predominantly govern immune system cascades and inflammatory activation. Because immune-mediated reactions drive colonic tissue damage in colitis and progressive bile duct destruction in cholangitis, this substantial overlap suggests that common genetic polymorphisms contribute to shared immune dysregulation, predisposing individuals to concurrent intestinal and biliary inflammation.

Transcriptomic screening of the Gene Expression Omnibus datasets exposed widespread expression alterations across both disorders. The differential expression pipeline identified 4189 differentially expressed genes in ulcerative colitis cohorts and 1384 in primary sclerosing cholangitis. Intersection analysis revealed 157 differentially expressed genes common between the two colitis datasets, alongside 56 genes significantly dysregulated in both colitis and cholangitis patients. The authors then conducted pairwise comparisons to integrate DisGeNET genetic variants with microarray transcriptomic profiles, identifying eleven genes common to both databases for ulcerative colitis and twenty-two for primary sclerosing cholangitis. Crucially, PTPN2 emerged as the only gene in the study shared between ulcerative colitis and primary sclerosing cholangitis at both the single-nucleotide polymorphism level and the differential expression level.

The dual involvement of PTPN2 highlights an important regulatory nexus bridging gut and liver inflammation. The PTPN2 gene encodes protein tyrosine phosphatase nonreceptor 2, also known as T-cell tyrosine phosphatase, an enzyme that dephosphorylates tyrosine residues to modulate diverse cell signaling molecules. Its target substrates include key tyrosine kinases such as the epidermal growth factor receptor, insulin receptor, Src family kinases, Janus kinases, and signal transducer and activator of transcription proteins, influencing cellular growth, division, and differentiation. In mucosal immunity, PTPN2 dephosphorylates T-cell receptor kinases to attenuate inflammation. Functional disruptions in PTPN2 promote naive T-helper cell maturation into inflammatory Th1 and Th17 lineages while dampening regulatory T-cell abundance, elevating inflammatory cytokines including interferon-gamma, interleukin-17, and interleukin-22. Prior studies have linked PTPN2 polymorphisms like rs12968719 and rs1893217 to cholangitis risk and gut dysbiosis, though the precise biological role of rs62097857 identified in this dataset warrants dedicated future investigation.

Functional enrichment analysis of the 56 shared differentially expressed genes using the Enrichr platform delineated 207 biological processes, 48 molecular functions, and 8 Kyoto Encyclopedia of Genes and Genomes pathways meeting significance thresholds. Biological process findings centered strongly on post-transcriptional processing, particularly mRNA splicing (GO:0000398 and GO:0000377) and general mRNA processing (GO:0006397), involving key genes such as YTHDC1, U2AF2, HNRNPA2B1, SNRPA1, SNU13, and PABPC1. The common genes also mapped to innate immunity, with BANF1, CEP63, and PTPN2 mediating negative regulation of innate immune responses, while CFH, BANF1, and CEP63 contributed to broader innate immune signaling. Molecular functions were heavily enriched for RNA binding and mRNA binding. Pathway enrichment identified the spliceosome, mRNA surveillance, and sulfur metabolism pathways as significantly associated with shared genes. The emergence of sulfur metabolism resonates with prior clinical observations connecting altered sulfur processing and elevated bacterial hydrogen sulfide with epithelial injury during colonic inflammation.

Protein-protein interaction modeling provided a physical map of the 56 common differentially expressed gene products. Using the STRING database and Cytoscape version 3.9.1, the researchers constructed an interaction network consisting of 56 nodes and 46 edges. Hub genes, defined as nodes displaying a connectivity degree greater than 5, comprised PABPC1, HNRNPA2B1, SNU13, NOP56, and SNRPA1. Subnetwork clustering using the MCODE plug-in isolated a top regulatory module of five interconnected genes: PABPC1, SNRPA1, NOP56, NHP2L1, and HNRNPA2B1. These module genes function cohesively in RNA modification, stability, and processing. PABPC1 attaches to poly(A) tails to maintain transcript stability and participate in translational repression complexes within activated macrophages. SNRPA1 constitutes a component of the U2 small nuclear ribonucleoprotein complex assisting early pre-mRNA splice site recognition, NOP56 processes precursor ribosomal RNA, NHP2L1 supports spliceosome assembly and telomere maintenance, and HNRNPA2B1 functions as an RNA methylation reader governing transcript degradation and macrophage polarization.

Given the prominent role of post-transcriptional machinery, the investigators constructed a competing endogenous RNA network regulating the top module. Searching miRTarBase revealed 94 microRNAs targeting the top module genes, though none were identified for HNRNPA2B1. Further querying of circBank yielded 200 circular RNAs targeting these microRNAs, which the authors assembled into a regulatory network comprising four messenger RNAs, 94 microRNAs, and 200 circular RNAs. Degree analysis via CytoHubba identified thirty major hub nodes, led by PABPC1, hsa-miR-6884-5p, NHP2L1, hsa-miR-4728-5p, hsa-miR-1273g-3p, hsa-miR-23b-3p, and SNRPA1. Screening miRNet revealed 590 long noncoding RNAs interacting with 38 of these microRNAs, though no single noncoding RNA was universally shared. While specific hubs like hsa-miR-23b-3p have been previously documented in Crohn’s disease colonic tissue, none matched microRNAs previously reported in extracellular vesicles from cholangitis patients, suggesting that distinct regulatory noncoding circuits may mediate the progression from colitis toward biliary disease.

Upstream transcriptional control and multi-tissue co-expression networks provided additional context regarding module regulation. Querying the hTFtarget database revealed numerous transcription factors acting on the top module genes, with 90 common factors capable of co-regulating all five module components. To trace co-expression across target organs, the authors queried the HIPPIE database to construct co-expression networks across human colon and liver tissues at high confidence. This analysis revealed three distinct subnetworks joined by shared bridging genes. Two genes, CUL3 and DHX15, connected across all three subnetworks, with DHX15 demonstrating the strongest network association. DHX15 encodes a putative ATP-dependent RNA helicase active in pre-mRNA splicing, reinforcing the functional enrichment findings. CUL3 encodes cullin-3, a core scaffold of the cullin-RING E3 ubiquitin ligase complex that targets defective proteins for proteasomal degradation. This ubiquitin-proteasome pathway regulates vital cellular processes, including cell cycle timing, division, and protein quality control in both gastrointestinal and hepatic tissues.

Finally, the researchers evaluated candidate therapeutics and summarized key limitations. Querying the Drug Gene Interaction Database identified four drugs interacting with PABPC1: CHEMBL585964, CHEMBL592588, CHEMBL589711, and ditolylguanidine, a sigma receptor ligand shown to modulate voltage-gated sodium channels in cardiac models. For downregulated PTPN2, eight candidate interacting compounds were identified, including dipicolinic acid, cloxyquin, and CHEMBL compounds. Notably, cloxyquin activates the TRESK potassium channel, an ion channel that supports regulatory T-cell differentiation and T-cell receptor signaling, presenting potential immunomodulatory applications. However, the authors underscored that these findings derive entirely from computational database mining and retrospective peripheral blood microarray profiles without experimental in vitro or in vivo biological validation. The available datasets were limited in cohort size, necessitating cautious interpretation. Future prospective laboratory studies and tissue-based analyses will be required to confirm whether these identified genetic variants, noncoding RNA networks, and candidate targets can effectively guide diagnostic screening or prevent primary sclerosing cholangitis development in patients with ulcerative colitis.

Subject of Research: Bioinformatics analysis of shared molecular pathways between ulcerative colitis and primary sclerosing cholangitis

Article Title: Bioinformatics analysis reveals shared molecular pathways for relationship between ulcerative colitis and primary sclerosing cholangitis

Article References: Jalali, P., Rezaee, M., Yaghoobi, A., Piroozkhah, M., Zabihi, M. R., Aliyari, S., & Salehi, Z. (2025). Bioinformatics analysis reveals shared molecular pathways for relationship between ulcerative colitis and primary sclerosing cholangitis. Genomics & Informatics, 23(1), Article 12. https://doi.org/10.1186/s44342-025-00045-4

Image Credits: AI Generated

DOI: 10.1186/s44342-025-00045-4

Keywords: ulcerative colitis, primary sclerosing cholangitis, bioinformatics, PTPN2, gene expression, mRNA splicing, protein-protein interaction, ceRNA network, analysis, reveals, shared, molecular