Genome-wide expression profiling implicates a MAST3-regulated gene set in colonic mucosal inflammation of ulcerative colitis patients

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) presumably caused by dysregulated immune responses to the gut microbiota. Genetic association studies have implicated dozens of chromosomal regions or loci in IBD susceptibility. The next challenge is to explain the individual role of each of these modest effect loci in disease state. We have previously identified MAST3 as an IBD susceptibility gene through genetic fine-mapping of the 19p linkage region. Testing MAST3 in a reporter assay provided preliminary evidence that MAST3 modulates the activity of inflammation-related transcription factor nuclear factor kappa B (NF-κB). Here, we further characterized the function of MAST3 through an examination of the influence of the modulation of MAST3 expression on endogenous genome-wide expression patterns. More specifically, we looked at differential gene expression resulting from overexpression and knockdown of the MAST3 gene in epithelial and macrophage cell lines. We highlight a group of genes whose expression is modulated by MAST3 and correlate their expression with NF-κB activity. Their expression was found to be enriched in inflamed mucosal tissue of UC patients, confirming the importance of these genes in IBD. These MAST3-regulated genes are central to mucosal immune responses. Among them are pro-inflammatory cytokines (e.g. CCL20, IL8), regulators of NF-κB (e.g. TNFAIP3, LY96, NFKBIA), genes involved in interferon-induced defense against pathogen invasion (e.g. IFIT1, ISG15) and genes involved in cell adhesion and/or migration (e.g. CD44, TMOD1). Taken together, these results confirm MAST3 as a modulator of the inflammatory response through regulation of immune gene expression in the gut of IBD patients.

Altered expression of Tumor Necrosis Factor Alpha -Induced Protein 3 correlates with disease severity in Ulcerative Colitis

“…In our study, we report significant up-regulated expression of TNFAIP3 mRNA in UC patients as compared to controls. This is consistent with a previous finding that TNFAIP3 mRNA expression increases in inflamed tissues compared to non-inflamed tissues during UC 36 . This suggests that alteration in TNFAIP3 expression is an inherent feature of inflammation during UC.…”

From genetics of inflammatory bowel disease towards mechanistic insights

“…Furthermore, IBD genes interact, as highlighted by the discovery of a MAST3-regulated transcriptional program that broadly controls expression of inflammatory genes associated with NFkB activity, such as those induced by NOD2 and TLRs [27, 28]. It is now possible to discern the impact of genetic perturbation on transcriptional programs by employing RNAi-mediated knockdown of candidate genes followed by RNAseq.…”

IL12Rβ1: The cytokine receptor that we used to know

“…Human IL12RB1 is one such gene that epigenetically differs between individuals (107). IL12RB1 is on chromosome 19, which is among the most gene dense chromosomes, and the most homologous to other animals (108); in IL12RB1 ’s immediate vicinity are other positive regulators of DTH, including Mast3 (109), and Jak3 (110), and Ifi30 (111). In mice, transcription of IL12Rβ1 is driven by a promoter region that begins 2.5kb upstream of the il12rb1 start site (112).…”