Transcriptional dynamics of colorectal cancer risk associated variation at 11q23.1 correlate with tuft cell abundance and marker expression in silico

Abstract

Colorectal cancer (CRC) is characterised by heritable risk that is not well understood. Heritable, genetic variation at 11q23.1 is associated with increased colorectal cancer (CRC) risk, demonstrating eQTL effects on 3 cis- and 23 trans-eQTL targets. We sought to determine the relationship between 11q23.1 cis- and trans-eQTL target expression and test for potential cell-specificity. scRNAseq from 32,361 healthy colonic epithelial cells was aggregated and subject to weighted gene co-expression network analysis (WGCNA). One module (blue) included 19 trans-eQTL targets and was correlated with POU2AF2 expression only. Following unsupervised clustering of single cells, the expression of 19 trans-eQTL targets was greatest and most variable in cluster number 11, which transcriptionally resembled tuft cells. 14 trans-eQTL targets were found to demarcate this cluster, 11 of which were corroborated in a second dataset. Intra-cluster WGCNA and module preservation analysis then identified twelve 11q23.1 trans-eQTL targets to comprise a network that was specific to cluster 11. Finally, linear modelling and differential abundance testing showed 11q23.1 trans-eQTL target expression was predictive of cluster 11 abundance. Our findings suggest 11q23.1 trans-eQTL targets comprise a POU2AF2-related network that is likely tuft cell-specific and reduced expression of these genes correlates with reduced tuft cell abundance in silico.

Genetic mapping revealsPou2af2-dependent tuning of tuft cell differentiation and intestinal type 2 immunity

“…Intriguingly, Pou2f3 has been linked to several human cancers, including small cell lung cancer and colon cancer (37,38). Particularly relevant to our findings, SNPs in or near Pou2af2 have also been linked to colon cancer and tuft cell abundance through genome-wide association studies and in silico analysis (39,40). Further studies are needed to fully reveal the role of tuft cells and regulation of these genes in the context of human cancers and immunity.…”

Genetic mapping reveals Pou2af2/ OCA-T1–dependent tuning of tuft cell differentiation and intestinal type 2 immunity

“…Pou2f3 has been linked to several human cancers, including small cell lung cancer and colon cancer ( 37 , 38 ). Particularly relevant to our findings, SNPs in or near Pou2af2 have also been linked to colon cancer and tuft cell abundance through genome-wide association studies and in silico analysis ( 39 , 40 ). Further studies are needed to fully reveal the role of tuft cells and regulation of these genes in the context of human cancers and immunity.…”

A short 3’UTR motif regulates gene expression in bilaterians

“…To investigate this, we searched for the occurrence of single nucleotide polymorphisms (SNPs) in the most conserved TTGTTTT region of USE-containing genes (Figure 8A). We found 2 genes containing a SNP in the most conserved area of the USE that each of these respective SNPs have been associated to the development of a specific disease (rs3087967; C11orf53/POU2AF2-Malignant tumor of colon [39]) or trait (rs149940960-GREB1-Alanine aminotransferase measurement [40]) (Figure 8B). Importantly, one of these genes, POU2AF2/C11orf53 has been recently described to act as a coactivator of POU2F3 to maintain chromatin accessibility, therefore having the potential to control genetic programs [41].…”