Genes in Inflammatory Bowel Disease-Associated Risk Loci Demonstrate Genotype-, Tissue-, and Inflammation-Specific Patterns of Expression in Terminal Ileum and Colon Mucosal Tissue
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73094 | GEO | 2016/08/10
SECONDARY ACCESSION(S): PRJNA296034
REPOSITORIES: GEO
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Population-based association studies have identified many genetic risk loci for coronary artery disease (CAD), but it is often unclear how genes within these loci are linked to CAD. Here, we performed interaction proteomics for 11 CAD-risk genes to map their protein-protein interactions (PPIs) in human vascular cells and elucidate their biological relevance in CAD pathogenesis. The PPI networks contain many protein interactions that are outside of known biology in the vasculature and are enriched for genes involved in immunity-related and arterial-wall-specific mechanisms. Furthermore, several PPI networks derived from smooth muscle cells are significantly enriched for genetic variants associated with CAD and related vascular phenotypes. Finally, our networks identified 61 genes that are found in genetic loci associated with risk of CAD, prioritizing them as the causal candidates within these loci. Together, our results indicate that the PPI networks we have generated are a rich resource for guiding future research into the molecular pathogenesis of CAD.
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Project description: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 have 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. Comparing the genes whose expression was modulated by each ORF, as well as the functions enriched within these gene lists, 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 known for these genes. These analyses also identified two major clusters of genes with shared impact on the transcriptome: 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 of these clusters highlighted how multiple IBD gene candidates impact on epithelial structure and function, including the protection of the mucosa from intestinal 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.
2021-10-16 | GSE186001 | GEO
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2013-12-06 | E-GEOD-51425 | biostudies-arrayexpress
Project description:Background: Genome wide association studies (GWASs) have revealed many susceptibility loci for complex genetic diseases. For most loci the causal genes have not been identified. The identification of candidate genes is currently mainly based genes that localize close to or within the identified loci. We have recently shown that 92 of the 163 Inflammatory Bowel Disease (IBD)-loci co-localize with noncoding DNA regulatory elements (DRE). Mutations in DRE can contribute to the pathogenesis of IBD through dysregulation of gene expression. Consequently, genes that are regulated by these 92 DRE are to be considered as candidate genes. We developed a novel approach for candidate gene identification that is based on DNA regulatory mechanisms.Results: By using circular chromosome conformation capture-sequencing (4C-seq), we have identified genomic regions that physically interact with the 92 DRE that were found at IBD susceptibility loci. Since the activity of regulatory elements is cell type specific, 4C-seq was performed in monocytes, lymphocytes and intestinal epithelial cells. Altogether, we identified 902 novel IBD candidate genes. These genes include genes specific for one of the IBD subtypes and many noteworthy genes like ATG9A and IL10RA. We show that the expression of many novel candidate genes is genotype dependent and that these genes are upregulated during intestinal inflammation in IBD. Pathway analyses further identified HNF4α as a potential key upstream regulator of the IBD candidate genes.Conclusions: In this study, 4C-seq is used to systematically analyze chromatin interactions at IBD susceptibility loci that localize to regulatory DNA We reveal many novel and relevant IBD candidate genes, pathways and regulators. Our approach complements classical candidate gene identification, links novel genes to IBD and can be applied to any existing GWAS data.
2016-11-03 | GSE89441 | GEO
Project description:Genome-wide association studies (GWAS) have identified over 300 loci associated with the inflammatory bowel diseases (IBD), but putative causal genes for most are unknown. We conducted the largest disease-focused expression quantitative trait loci (eQTL) analysis using colon tissue from 252 IBD patients to determine genetic effects on gene expression and potential contribution to IBD. Combined with two non-IBD colon eQTL studies, we identified 194 potential target genes for 108 GWAS loci. eQTL in IBD tissue were enriched for IBD GWAS loci colocalizations, provided novel evidence for IBD-associated genes such as ABO and TNFRSF14, and identified additional target genes compared to non-IBD tissue eQTL. IBD-associated eQTL unique to diseased tissue had distinct regulatory and functional characteristics with increased effect sizes. Together, these highlight the importance of eQTL studies in diseased tissue for understanding functional consequences of genetic variants, and elucidating molecular mechanisms and regulation of key genes involved in IBD.
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2015-04-10 | E-GEOD-67106 | biostudies-arrayexpress
Project description:Objective The imbalance between Th17 cells and regulatory T cells in the gut of inflammatory bowel disease (IBD) patients promotes intestinal epithelial cell damage. In this scenario, T helper cell lineage commitment is accompanied by dynamic changes to the chromatin that facilitate, enforce or repress gene expression patterns and ultimately promote the induction and maintenance of dysregulated intestinal CD4 T cells. Design Here, we characterized the chromatin landscape and the heterogeneity of CD4 T cells from blood samples and biopsies of IBD patients using in house generated ATAC-Seq and single cell RNA-Seq libraries as well as publicly available datasets. Results We found that chromatin accessibility profiles specific to CD4 T cells from inflamed intestinal biopsies associate to inflammatory genes capable of promoting γδT, NK, T and B cell activation and proliferation. Our data show that the chromatin accessibility changes of CD4 T cells are associated with a higher predominance of pathogenic Th17 cells (pTh17 cells) in inflamed biopsies of IBD patients. In addition, we found that IBD risk loci in CD4 T cells are colocalized with accessible chromatin changes near pTh17-related genes. For instance, the IBD risk locus rs12942547 lies within an intronic STAT3 region enriched in areas of active intestinal inflammation from IBD patients. A similar profile was observed in a region near IL23R. Moreover, single cell RNA-Seq analysis of CD4 T cells from patient biopsies shows a population of CD4 T cells that resembles pTh17 cells with co-expression of Th1 and Th17 transcriptional programs, including a cytotoxic gene signature. Conclusion Altogether, our data suggest that cytotoxic pTh17 cells are associated with intestinal inflammation of IBD patients and specifically associate some IBD genetic variants with this CD4 T cell subset.
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