Dissection of the inflammatory bowel disease transcriptome using genome-wide cDNA microarrays.
BACKGROUND
The differential pathophysiologic mechanisms that trigger and maintain the two forms of inflammatory bowel disease (IBD), Crohn disease (CD), and ulcerative colitis (UC) are only partially understood. cDNA microarrays can be used to decipher gene regulation events at a genome-wide level and to identify novel unknown genes that might be involved in perpetuating inflammatory disease progression.


RESULTS
High-density cDNA microarrays representing 33,792 UniGene clusters were prepared. Biopsies were taken from the sigmoid colon of normal controls (n = 11), CD patients (n = 10) and UC patients (n = 10). 33P-radiolabeled cDNA from purified poly(A)+ RNA extracted from biopsies (unpooled) was hybridized to the arrays. We identified 500 and 272 transcripts differentially regulated in CD and UC, respectively. Interesting hits were independently verified by real-time PCR in a second sample of 100 individuals, and immunohistochemistry was used for exemplary localization. The main findings point to novel molecules important in abnormal immune regulation and the highly disturbed cell biology of colonic epithelial cells in IBD pathogenesis, e.g., CYLD (cylindromatosis, turban tumor syndrome) and CDH11 (cadherin 11, type 2). By the nature of the array setup, many of the genes identified were to our knowledge previously uncharacterized, and prediction of the putative function of a subsection of these genes indicate that some could be involved in early events in disease pathophysiology.


CONCLUSIONS
A comprehensive set of candidate genes not previously associated with IBD was revealed, which underlines the polygenic and complex nature of the disease. It points out substantial differences in pathophysiology between CD and UC. The multiple unknown genes identified may stimulate new research in the fields of barrier mechanisms and cell signalling in the context of IBD, and ultimately new therapeutic approaches.
Costello
Christine M
CM
Institute for Clinical Molecular Biology, University Hospital Schleswig Holstein, Christian-Albrechts University of Kiel, Kiel, Germany.
Mah
Nancy
N
Häsler
Robert
R
Rosenstiel
Philip
P
Waetzig
Georg H
GH
Hahn
Andreas
A
Lu
Tim
T
Gurbuz
Yesim
Y
Nikolaus
Susanna
S
Albrecht
Mario
M
Hampe
Jochen
J
Lucius
Ralph
R
Klöppel
Günther
G
Eickhoff
Holger
H
Lehrach
Hans
H
Lengauer
Thomas
T
Schreiber
Stefan
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D025521:Tumor Suppressor Proteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD