Functional screen of inflammatory bowel disease genes reveals key epithelial functions

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 identif...

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Autores principales:	Jessy Carol Ntunzwenimana, Gabrielle Boucher, Jean Paquette, Hugues Gosselin, Azadeh Alikashani, Nicolas Morin, Claudine Beauchamp, Louise Thauvette, Marie-Ève Rivard, Frédérique Dupuis, Sonia Deschênes, Sylvain Foisy, Frédéric Latour, Geneviève Lavallée, Mark J. Daly, Ramnik J. Xavier, the iGenoMed Consortium, Guy Charron, Philippe Goyette, John D. Rioux
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Inflammatory bowel diseases Type I interferon response Mucosal immunity Secretory immunoglobulins Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/8469a01eca954f73a71584a0462d259d
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spelling	oai:doaj.org-article:8469a01eca954f73a71584a0462d259d2021-11-14T12:27:37ZFunctional screen of inflammatory bowel disease genes reveals key epithelial functions10.1186/s13073-021-00996-71756-994Xhttps://doaj.org/article/8469a01eca954f73a71584a0462d259d2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13073-021-00996-7https://doaj.org/toc/1756-994XAbstract 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.Jessy Carol NtunzwenimanaGabrielle BoucherJean PaquetteHugues GosselinAzadeh AlikashaniNicolas MorinClaudine BeauchampLouise ThauvetteMarie-Ève RivardFrédérique DupuisSonia DeschênesSylvain FoisyFrédéric LatourGeneviève LavalléeMark J. DalyRamnik J. Xavierthe iGenoMed ConsortiumGuy CharronPhilippe GoyetteJohn D. RiouxBMCarticleInflammatory bowel diseasesType I interferon responseMucosal immunitySecretory immunoglobulinsMedicineRGeneticsQH426-470ENGenome Medicine, Vol 13, Iss 1, Pp 1-21 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Inflammatory bowel diseases Type I interferon response Mucosal immunity Secretory immunoglobulins Medicine R Genetics QH426-470
spellingShingle	Inflammatory bowel diseases Type I interferon response Mucosal immunity Secretory immunoglobulins Medicine R Genetics QH426-470 Jessy Carol Ntunzwenimana Gabrielle Boucher Jean Paquette Hugues Gosselin Azadeh Alikashani Nicolas Morin Claudine Beauchamp Louise Thauvette Marie-Ève Rivard Frédérique Dupuis Sonia Deschênes Sylvain Foisy Frédéric Latour Geneviève Lavallée Mark J. Daly Ramnik J. Xavier the iGenoMed Consortium Guy Charron Philippe Goyette John D. Rioux Functional screen of inflammatory bowel disease genes reveals key epithelial functions
description	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.
format	article
author	Jessy Carol Ntunzwenimana Gabrielle Boucher Jean Paquette Hugues Gosselin Azadeh Alikashani Nicolas Morin Claudine Beauchamp Louise Thauvette Marie-Ève Rivard Frédérique Dupuis Sonia Deschênes Sylvain Foisy Frédéric Latour Geneviève Lavallée Mark J. Daly Ramnik J. Xavier the iGenoMed Consortium Guy Charron Philippe Goyette John D. Rioux
author_facet	Jessy Carol Ntunzwenimana Gabrielle Boucher Jean Paquette Hugues Gosselin Azadeh Alikashani Nicolas Morin Claudine Beauchamp Louise Thauvette Marie-Ève Rivard Frédérique Dupuis Sonia Deschênes Sylvain Foisy Frédéric Latour Geneviève Lavallée Mark J. Daly Ramnik J. Xavier the iGenoMed Consortium Guy Charron Philippe Goyette John D. Rioux
author_sort	Jessy Carol Ntunzwenimana
title	Functional screen of inflammatory bowel disease genes reveals key epithelial functions
title_short	Functional screen of inflammatory bowel disease genes reveals key epithelial functions
title_full	Functional screen of inflammatory bowel disease genes reveals key epithelial functions
title_fullStr	Functional screen of inflammatory bowel disease genes reveals key epithelial functions
title_full_unstemmed	Functional screen of inflammatory bowel disease genes reveals key epithelial functions
title_sort	functional screen of inflammatory bowel disease genes reveals key epithelial functions
publisher	BMC
publishDate	2021
url	https://doaj.org/article/8469a01eca954f73a71584a0462d259d
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Functional screen of inflammatory bowel disease genes reveals key epithelial functions

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