Systematic analysis of circadian genes using genome-wide cDNA microarrays in the inflammatory bowel disease transcriptome

Abstract

Simultaneous analysis of the transcripts of thousands of genes by cDNA microarrays allows the identification of genetic regulatory mechanisms involved in disease pathophysiology. The circadian clock circuitry controls essential cell processes and the functioning of organ systems, which are characterized by rhythmic variations with 24-hour periodicity. The derangement of these processes is involved in the basic mechanisms of inflammatory, metabolic, degenerative and neoplastic diseases. We evaluated by genome-wide cDNA microarray analysis the transcriptome of endoscopic mucosal biopsies of patients with inflammatory bowel diseases (IBD) focusing on the expression of circadian genes in Crohn’s disease (CD) and ulcerative colitis (UC). Twenty-nine IBD patients (15 with CD and 14 with UC) were enrolled and mucosal biopsies were sampled at either inflamed or adjacent non-inflamed areas of the colon. A total of 150 circadian genes involved in pathways controlling crucial cell processes and tissue functions were investigated. In CD specimens 50 genes were differentially expressed, and 21 genes resulted up-regulated when compared to healthy colonic mucosa. In UC specimens 50 genes were differentially expressed, and 27 genes resulted up-regulated when compared to healthy colonic mucosa. Among the core clock genes ARNTL2 and RORA were up-regulated, while CSNK2B, NPAS2, PER1 and PER3 were down-regulated in CD specimens. Conversely, ARNTL2, CRY1, CSNK1E, RORA and TIPIN were up-regulated, while NR1D2 and PER3 were down-regulated in UC. In conclusion, in CD and UC patients there are differences in the expression of circadian genes between normal and diseased intestinal mucosa. The deregulated genes evidenced by transcriptome analysis in the major IBDs may play a crucial role in the pathophysiological mechanisms and may suggest novel therapeutic approaches.

• Circadian rhythm
• clock gene
• Crohn’s disease
• inflammatory bowel disease
• ulcerative colitis

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. The study was supported by the “5 × 1000” voluntary contribution and by a grant from the Italian Ministry of Health to OP and AL through the Division of Gastroenterology (GR-2008-1144485, RC1202GA39 and RC1302GA33) and to GM through the Division of Internal Medicine and Chronobiology Unit (RC1201ME04, RC1203ME46, RC1302ME31, RC1403ME50), IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy. The study was co-funded by a grant from Fondazione Cassa di Risparmio di Puglia (F.C.R.P.) (CI: 3102011041457/RV12GAMICI). This work was partially supported by grants from Regione Puglia PO FESR 2007-2013 Progetto BISIMANE (Cod. n. 44), Progetto FIRB RBAP11B2SX, Progetto di Ricerca Finalizzata 2009 RF/2009-1471624.

Supplementary material available online.