Functional screen of inflammatory bowel disease genes reveals key epithelial functions
-
Published:2021-11-11
Issue:1
Volume:13
Page:
-
ISSN:1756-994X
-
Container-title:Genome Medicine
-
language:en
-
Short-container-title:Genome Med
Author:
Ntunzwenimana Jessy Carol, Boucher Gabrielle, Paquette Jean, Gosselin Hugues, Alikashani Azadeh, Morin Nicolas, Beauchamp Claudine, Thauvette Louise, Rivard Marie-Ève, Dupuis Frédérique, Deschênes Sonia, Foisy Sylvain, Latour Frédéric, Lavallée Geneviève, Daly Mark J., Xavier Ramnik J., Bitton Alain, Boucher Gabrielle, Charron Guy, Rosiers Christine Des, Forest Anik, Goyette Philippe, Ivison Sabine, Joseph Lawrence, Kohen Rita, Lachaine Jean, Lesage Sylvie, Levings Megan K., Rioux John D., Legault Julie Thompson, Vachon Luc, Veilleux Sophie, White-Guay Brian, Charron Guy, Goyette Philippe, Rioux John D.ORCID,
Abstract
Abstract
Background
Genetic studies have been tremendously successful in identifying genomic regions associated with a wide variety of phenotypes, although the success of these studies in identifying causal genes, their variants, and their functional impacts has been more limited.
Methods
We identified 145 genes from IBD-associated genomic loci having endogenous expression within the intestinal epithelial cell compartment. We evaluated the impact of lentiviral transfer of the open reading frame (ORF) of these IBD genes into the HT-29 intestinal epithelial cell line via transcriptomic analyses. By comparing the genes in which expression was modulated by each ORF, as well as the functions enriched within these gene lists, we identified ORFs with shared impacts and their putative disease-relevant biological functions.
Results
Analysis of the transcriptomic data for cell lines expressing the ORFs for known causal genes such as HNF4a, IFIH1, and SMAD3 identified functions consistent with what is already known for these genes. These analyses also identified two major clusters of genes: Cluster 1 contained the known IBD causal genes IFIH1, SBNO2, NFKB1, and NOD2, as well as genes from other IBD loci (ZFP36L1, IRF1, GIGYF1, OTUD3, AIRE and PITX1), whereas Cluster 2 contained the known causal gene KSR1 and implicated DUSP16 from another IBD locus. Our analyses highlight how multiple IBD gene candidates can impact on epithelial structure and function, including the protection of the mucosa from intestinal microbiota, and demonstrate that DUSP16 acts a regulator of MAPK activity and contributes to mucosal defense, in part via its regulation of the polymeric immunoglobulin receptor, involved in the protection of the intestinal mucosa from enteric microbiota.
Conclusions
This functional screen, based on expressing IBD genes within an appropriate cellular context, in this instance intestinal epithelial cells, resulted in changes to the cell’s transcriptome that are relevant to their endogenous biological function(s). This not only helped in identifying likely causal genes within genetic loci but also provided insight into their biological functions. Furthermore, this work has highlighted the central role of intestinal epithelial cells in IBD pathophysiology, providing a scientific rationale for a drug development strategy that targets epithelial functions in addition to the current therapies targeting immune functions.
Funder
genome canada national institutes of health canada research chairs canada foundation for innovation canadian institutes of health research
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Reference90 articles.
1. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24. https://doi.org/10.1038/nature11582. 2. Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979–86. https://doi.org/10.1038/ng.3359. 3. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314(5804):1461–3. https://doi.org/10.1126/science.1135245. 4. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39(5):596–604. https://doi.org/10.1038/ng2032. 5. Beaudoin M, Goyette P, Boucher G, Lo KS, Rivas MA, Stevens C, et al. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genet. 2013;9(9):e1003723. https://doi.org/10.1371/journal.pgen.1003723.
Cited by
17 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|