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Single-Cell Analyses Elucidate the Cellular and Molecular Landscape of Ulcerative Colitis

ABSTRACT: Inflammatory bowel disease (IBD) encompasses a spectrum of complex intestinal disorders characterized by dysregulated host innate and adaptive immune responses to gut microbiota in genetically susceptible hosts. We generated an integrated single-cell (scRNA-seq, scTCR-seq, and scBCR-seq) resource dataset that revealed key cellular components and cell states of the gastrointestinal mucosal and peripheral immune systems in health and ulcerative colitis (UC).

ORGANISM(S): Homo sapiens

PROVIDER: GSE125527 | GEO | 2020/07/16

REPOSITORIES: GEO

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Project description:Background & Aims: Inflammatory bowel diseases (IBD) are clinically manifested as ulcerative colitis (UC) and Crohn’s Disease (CD). Novel high throughput technologies revealed new categories of genes, including the long non-coding RNAs (lncRNAs), which have been involved in the pathogenesis of different human diseases; however the role and function of lncRNAs in the UC pathogenesis has not been evaluated. Methods: The gene expression patterns for both non-coding (lncRNAs) and coding (mRNA) transcripts were profiled in UC (n=8) and control (n=7) patients by ArrayStar assays. The differentially expressed genes were used to develop lncRNA signatures in UC samples. Ingenuity Software Analysis (IPA) program was used to identify the up-stream regulators of IFNG-AS1. Jurkat T cells were activated by PMA/ionomycin and IFNG and TNF protein levels were assessed by ELISA assay. Two anti-sense molecules were designed and used to block IFNG-AS1 expression levels. Colonic tissues from TNBS-treated and IL10-/- mice were used to extract RNA and examine INFG-AS1 expression by real-time PCR. Results: A unique set of lncRNAs was found to be differentially expressed between UC (n=15) and control samples (n=16). Of these, IFNG-AS1 was among the highest statistically significant lncRNAs (fold change: 5.27, p-value: 7.07E-06). Bioinformatic analyses showed that IFNG-AS1 was associated with the IBD susceptibility loci SNP rs7134599 and its genomic location is adjacent to the inflammatory cytokine, interferon-gamma (IFNG). Using the TNBS and IL10-/- mouse models of colitis, we found increased colonic expression of this lncRNA during active colitis. Utilizing the Jurkat T cell model system, we explored the mechanisms of action and found that IFNG-AS1 can positively regulate IFNG expression. Conclusions: Novel lncRNA signatures were identified to differentiate UC patients with active disease, in remission and control subjects. A subset of these lncRNAs was found to be associated with the clinically validated IBD susceptibility loci. IFNG-AS1 was one of these differentially expressed lncRNAs in UC patients and was found to regulate the key inflammatory cytokine, IFNG, in CD4 T cells. Taken together, our study revealed novel lncRNA signatures deregulated in ulcerative colitis and identified IFNG-AS1 as a novel regulator of IFNG inflammatory responses, suggesting the potential importance of non-coding RNA mechanisms on regulation of IBD-related inflammatory responses.

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Single-Cell Analyses Elucidate the Cellular and Molecular Landscape of Ulcerative Colitis

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