Presenter of 2 Presentations
EARLY ONSET IBD (ID 1522)
G-O078 - MUCOSAL CLOCK AND INFLAMMATION REGULATORY GENES ARE DISRUPTED IN TREATMENT NAÏVE PEDIATRIC PATIENTS WITH ULCERATIVE COLITIS (ID 670)
Abstract
Objectives and Study
The human circadian clock is present in all cells. It includes the CLOCK and BMAL1 genes which heterodimerize to mediate transcription of many genes, including their negative regulators: PERIODs (PERs) and CRYPTOCHROMEs (CRYs). We have shown that patients with active ulcerative colitis (UC) display misalignment of the molecular clock that reverts to normal following effective treatment. Several circadian clock genes also function as anti-inflammatory regulators. For example, RORα, PPARα and PPARγ positively regulate the expression of both the clock mechanism and that of IkB, the NFkB suppressor. Similarly, PCG1α induces transcription of IL10. Our aim was to characterize the expression of these clock genes and regulators and determine their correlations in UC patients.
Methods
Using whole transcriptome RNA sequencing from the IBD Transcriptome and Metatranscriptome Meta-Analysis platform(TaMMA IBD), we compared rectal biopsy gene expression levels and correlations of AMPK, BMAL1, CLOCK, CRY1, CRY2, PER1, PER2, PCG1α, PPARα, PPARγ, REV-ERBα, RORα, RORγ and SIRT1 in 206 treatment naïve pediatric UC patients (age 12.9±3.2; 54% male) and 20 healthy controls (age 13.9±3.3; 45% male).
Results
Core clock genes, BMAL (p<0.0001), CLOCK (p<0.01) and CRY1 (p<0.0001), and the anti-inflammatory regulatory gene RORα (p<0.0001) were upregulated in patients compared to controls. In contrast, expression of other anti-inflammatory regulatory genes, PCG1α (p<0.0001), PPARα (p<0.01), PPARγ (p<0.0001) and RORγ (p<0.0001) were decreased in patients. Clock gene expression of healthy controls showed discordant correlations compared to UC patients, e.g., BMAL/REV-ERBα and PPARγ/REV-ERBα correlations were inverted between controls and patients (r=-0.44 vs. r=0.13 and r =-0.4 vs. r=0.3, respectively).
Conclusions
Core clock gene expression was disrupted, and anti-inflammatory regulatory gene expression was decreased in patients with active UC. The discordant correlations in UC patients highlight clock disruption in active inflammation. Since these clock regulators also ameliorate inflammation, their reduced expression may explain not only clock dysregulation but also increased tissue inflammation.
