Rajasekaran Vidya, Harris Bradley T, Osborn Ruby T, Smillie Claire, Donnelly Kevin, Bacou Marion, Esiri-Bloom Edward, Ooi Li-Yin, Allan Morven, Walker Marion, Reid Stuart, Meynert Alison, Grimes Graeme, Blackmur James P, Vaughan-Shaw Peter G, Law Philip J, Fernández-Rozadilla Ceres, Tomlinson Ian, Houlston Richard S, Myant Kevin B, Din Farhat Vn, Timofeeva Maria, Dunlop Malcolm G, Farrington Susan M
CRUK Edinburgh Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
Gut. 2025 Apr 7;74(5):787-803. doi: 10.1136/gutjnl-2024-332121.
Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on , and genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk.
Undertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.
We employ analysis of RNA sequencing, single-cell RNA sequencing, chromatin immunoprecipitation sequencing and single-cell ATAC sequencing data to identify, prioritise and characterise the genes that contribute to CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.
We establish rs3087967 as a prime eQTL variant at 11q23.1, colocalising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell-specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the mouse phenotype on abrogation of expression specifically.
We demonstrate that genotype at rs3087967 controls a portfolio of genes through misregulation of is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.
11q23.1处的常见基因变异与结直肠癌（CRC）风险相关，对 、 和 基因发挥局部表达数量性状位点（顺式-eQTL）效应。然而，复杂的连锁不平衡和相关表达阻碍了对基因变异赋予潜在CRC风险机制的阐明。
采用跨学科方法来理解11q23.1位点的变异如何赋予CRC风险。
我们运用RNA测序、单细胞RNA测序、染色质免疫沉淀测序和单细胞ATAC测序数据分析，以识别、排序和表征导致CRC风险的基因。我们进一步使用小鼠模型验证这些发现，并在人类结肠黏膜中证明了类似的效应。
我们确定rs3087967是11q23.1处的主要eQTL变异，与CRC风险共定位。此外，rs3087967影响21个远距离基因的表达，从而作为一个基因集的反式-eQTL枢纽，该基因集高度富集簇状细胞标志物。表观基因组分析表明POU2AF2通过与POU2F3相关的基因组调控控制簇状细胞特异性反式基因。免疫荧光证实rs3087967风险基因型（T）与人类结肠中的簇状细胞缺陷相关。CRISPR介导的小鼠种系中11q23.1风险位点基因的缺失，在特异性消除 表达时加剧了 小鼠的表型。
我们证明rs3087967处的基因型通过对 的错误调控控制一组基因， 是簇状细胞的主要转录激活因子，在小鼠模型中具有肿瘤抑制作用。因此，我们认为簇状细胞在大肠上皮中具有关键的肿瘤保护作用。
