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The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226875 | GEO | 2023/03/20

REPOSITORIES: GEO

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Project description:Inflammatory bowel disease (IBD) is a complex multi-factorial inflammatory disease with Crohn’s disease (CD) and ulcerative colitis (UC) being the two most common forms. A number of transcriptional profiling studies have provided compelling evidence that describe the role of protein-coding genes and microRNAs in modulating the immune responses in IBD. In the present study, we performed a genome-wide transcriptome profiling of lncRNAs and protein-coding genes in inflamed and non-inflamed colon pinch biopsies from the IBD patients using expression microarrays platform. In this study, we identified widespread dysregulation of lncRNAs and protein-coding genes in both inflamed and non-inflamed CD and UC compared to the healthy controls. In case of inflamed CD and UC (iCD and iUC), we identified 438 and 745 differentially expressed lncRNAs, respectively, while in case of the non-inflamed CD and UC (niCD and niUC), we identified 12 and 19 differentially expressed lncRNAs, respectively. We also observed significant enrichment (p-value < 0.001, Pearson’s Chi-squared test) for 96 differentially expressed lncRNAs and 154 protein-coding genes within the IBD susceptibility loci. Furthermore, we found strong positive expression correlations for the intersecting and cis-neighboring differentially expressed IBD loci-associated lncRNA-protein-coding gene pairs. The functional annotation analysis of differentially expressed genes revealed that they are involved in immune response, pro-inflammatory cytokine activity and MHC protein complex. The lncRNA expression profiling in both inflamed and non-inflamed CD and UC, successfully stratified IBD patients from the healthy controls. Taken together, the identified lncRNA transcriptional signature along with clinically relevant parameters suggests their potential as biomarkers in IBD. A total of 96 biopsy samples (including 6 samples used as technical replicates) extracted from different colonic locations from 45 patients (CD=13, UC=20, Controls=12) were profiled using Agilent Custom 8x60K format lncRNA expression microarray. In Gencode v15 lncRNA microarray design, each lncRNA transcript is targeted by two probes covering 22,001 lncRNA transcripts corresponding to 12,963 lncRNA genes. In addition, each array contains 17,535 randomly-selected protein-coding targets, of which 15,182 (unique 12,787) correspond to protein-coding genes.

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The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population

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