Abstract
Ulcerative colitis (UC) is a common inflammatory bowel disease (IBD) producing intestinal inflammation and tissue damage. The precise aetiology of UC remains unknown. In this study, we applied a rank-based expression profile comparative algorithm, gene set enrichment analysis (GSEA), to evaluate the expression profiles of UC patients and small interfering RNA (siRNA)-perturbed cells to predict proteins that might be essential in UC from publicly available expression profiles. We used quantitative PCR (qPCR) to characterize the expression levels of those genes predicted to be the most important for UC in dextran sodium sulphate (DSS)-induced colitic mice. We found that bromo-adjacent homology domain (BAHD1), a novel heterochromatinization factor in vertebrates, was the most downregulated gene. We further validated a potential role of BAHD1 as a regulatory factor for inflammation through the TNF signalling pathway in vitro. Our findings indicate that computational approaches leveraging public gene expression data can be used to infer potential genes or proteins for diseases, and BAHD1 might act as an indispensable factor in regulating the cellular inflammatory response in UC.
Highlights
Ulcerative colitis (UC) and Crohn’s disease (CD), the two main subtypes of inflammatory bowel disease (IBD), are immunologically mediated, idiopathic, chronic and relapsing diseases[1], the aetiology of which remains unclear
By examining the relationships between UC and the 106 small interfering RNA (siRNA) based on predicted distance scores, we identified major clusters of the entire data set [Fig. 1]
We picked out the top five genes whose single siRNA perturbations had the lowest distance values relative to UC, namely, EZH2, UPF1, FOXM1, NUDT6, BAHD1, and we investigated the mRNA levels of these most likely candidate genes in the dextran sodium sulphate (DSS)-induced colitis mouse model by quantitative PCR (qPCR)
Summary
Ulcerative colitis (UC) and Crohn’s disease (CD), the two main subtypes of inflammatory bowel disease (IBD), are immunologically mediated, idiopathic, chronic and relapsing diseases[1], the aetiology of which remains unclear. Gene expression microarrays, which are frequently and widely applied in clinical studies of human diseases, enable the measurement of genome-wide expression[8]. This method has been applied to investigate transcriptional signatures present in gastrointestinal tissue obtained from CD and UC patients for more than 10 years[9]. The majority of the genes identified by this method do not necessarily play critical roles in the biological processes under investigation For this reason, we adopted a systematic computational in silico approach to predict novel genes or proteins on the basis of comprehensive testing of molecular signatures in siRNA-disease pairs: a pattern-matching strategy based on GSEA to more www.nature.com/scientificreports/. As it has not been previously described to have efficacy for UC or any related disorder of inflammation in the gastrointestinal tract, we evaluated the efficacy of BAHD1 in UC and explored its effect on the human epithelial colorectal adenocarcinoma cell line Caco-2 exposed to inflammatory mediators and its related molecular mechanism
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