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Mucosal Genes Encoding Clock, Inflammation and Their Mutual Regulators Are Disrupted in Pediatric Patients with
Sapir Labes1, Oren Froy2, Yuval Tabach1
1Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem 91905, Israel.
Insights
Pediatric ulcerative colitis (UC) patients show disrupted circadian clock and inflammation gene expression. This disruption is linked to disease severity and abnormal immune responses in the gut lining.
Area of Science:
- Molecular Biology
- Immunology
- Chronobiology
Background:
- Ulcerative colitis (UC) is associated with circadian clock misalignment, impacting immune function.
- Understanding gene expression in treatment-naïve pediatric UC is crucial for identifying disease mechanisms.
Approach:
- Analyzed rectal biopsy transcriptomic data from two pediatric UC cohorts using the IBD TaMMA platform and R algorithms.
- Compared gene expression of clock genes, inflammatory genes, and their mutual regulators between UC patients and healthy controls.
Key Points:
- Significant upregulation of clock genes (BMAL1, CLOCK, PER1, CRY1) and inflammatory genes (IκB, IL10, NFκB1, NFκB2, IL6, TNFα) in active UC patients.
- Downregulation of mutual regulator genes (RORα, RORγ, PGC1α, PPARα, PPARγ) observed in UC patients.
- Gene expression patterns were uniform in healthy controls but highly variable in UC patients, correlating with disease severity and endoscopic scores.
Conclusions:
- Disrupted clock gene expression in active UC is linked to abnormal mucosal immune responses.
- Aberrant expression of clock, inflammation, and regulatory genes may contribute to active UC pathogenesis.
Abstract:
Patients with active ulcerative colitis (UC) display a misalignment of the circadian clock, which plays a vital role in various immune functions. Our aim was to characterize the expression of clock and inflammation genes, and their mutual regulatory genes in treatment-naïve pediatric patients with UC. Using the Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) platform and R algorithms, we analyzed rectal biopsy transcriptomic data from two cohorts (206 patients with UC vs. 20 healthy controls from the GSE-109142 study, and 43 patients with UC vs. 55 healthy controls from the GSE-117993 study). We compared gene expression levels and correlation of clock genes (BMAL1, CLOCK, PER1, PER2, CRY1, CRY2), inflammatory genes (IκB, IL10, NFκB1, NFκB2, IL6, TNFα) and their mutual regulatory genes (RORα, RORγ, REV-ERBα, PGC1α, PPARα, PPARγ, AMPK, SIRT1) in patients with active UC and healthy controls. The clock genes BMAL1, CLOCK, PER1 and CRY1 and the inflammatory genes IκB, IL10, NFκB1, NFκB2, IL6 and TNFα were significantly upregulated in patients with active UC. The genes encoding the mutual regulators RORα, RORγ, PGC1α, PPARα and PPARγ were significantly downregulated in patients with UC. A uniform pattern of gene expression was found in healthy controls compared to the highly variable expression pattern in patients with UC. Among the healthy controls, inflammatory genes were positively correlated with clock genes and they all showed reduced expression. The difference in gene expression levels was associated with disease severity and endoscopic score but not with histological score. In patients with active UC, clock gene disruption is associated with abnormal mucosal immune response. Disrupted expression of genes encoding clock, inflammation and their mutual regulators together may play a role in active UC.
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