Cell Type-Specific Induction of Inflammation-Associated Genes in Crohn’s Disease and Colorectal Cancer

Abstract

Based on the rapid increase in incidence of inflammatory bowel disease (IBD), the identification of susceptibility genes and cell populations contributing to this condition is essential. Previous studies suggested multiple genes associated with the susceptibility of IBD; however, due to the analysis of whole-tissue samples, the contribution of individual cell populations remains widely unresolved. Single-cell RNA sequencing (scRNA-seq) provides the opportunity to identify underlying cellular populations. We determined the enrichment of Crohn’s disease (CD)-induced genes in a publicly available Crohn’s disease scRNA-seq dataset and detected the strongest induction of these genes in innate lymphoid cells (ILC1), highly activated T cells and dendritic cells, pericytes and activated fibroblasts, as well as epithelial cells. Notably, these genes were highly enriched in IBD-associated neoplasia, as well as sporadic colorectal cancer (CRC). Indeed, the same six cell populations displayed an upregulation of CD-induced genes in a CRC scRNA-seq dataset. Finally, after integrating and harmonizing the CD and CRC scRNA-seq data, we demonstrated that these six cell types display a gradual increase in gene expression levels from a healthy state to an inflammatory and tumorous state. Together, we identified cell populations that specifically upregulate CD-induced genes in CD and CRC patients and could, therefore, contribute to inflammation-associated tumor development.

High-resolution promoter interaction analysis in Type 3 Innate Lymphoid Cells implicates Batten Disease geneCLN3in Crohn’s Disease aetiology

“…Excluding nine genes whose tissue specificity could not be ascertained due to differences between study designs (see Methods), we found that over half of the remaining ILC3 PIR-prioritised genes (34/61) could also be prioritised based on Javierre et al PIRs (Table S9). This result is consistent with the involvement of multiple immune cell types in mediating CD risk 76,77 . In contrast, 27/61 genes could only be prioritised using ILC3 PIRs.…”

Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

“…To resolve this limitation, new techniques have allowed the study of single-cell-specific transcriptional profiles. For example, single-cell RNA sequencing (scRNA-seq) and high-dimensional protein analyses, such as mass cytometry and multichannel spectral cytometry, have defined IBD-linked profiles and detected cell subpopulations that are elevated or diminished in IBD, particularly populations of fibroblasts [ 10 ], epithelial cells [ 9 ], and immune cells [ 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 ].…”

Contextual AI models for single-cell protein biology

“…Here, we focus on modeling the therapeutic potential of proteins across cell types for therapeutic areas with cell type-specific mechanisms of action (Figure 4). Certain cell types are known to play crucial and distinct roles in the disease pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) therapeutic areas [58,60,[77][78][79][80][81][82][83][84][85]. There is currently no cure for either types of conditions, and the medications prescribed to mitigate the symptoms can lead to undesired side effects [86][87][88][89][90].…”