Background Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2 , COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk. Objective Undertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk. Design 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. Results 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 ApcMin/+ mouse phenotype on abrogation of Pou2af2 expression specifically. Conclusion We demonstrate that genotype at rs3087967 controls a portfolio of genes through misregulation of POU2AF2. POU2AF2 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. All data relevant to the study are included in the article or uploaded as supplementary information. NA.

中文翻译：

---

11q23.1 的遗传变异通过结肠簇状细胞转录激活因子失调赋予结直肠癌风险POU2AF2


背景 11q23.1 的常见遗传变异与结直肠癌 （CRC） 风险相关，对 POU2AF2 、 COLCA1 和 POU2AF3 基因产生局部表达数量性状基因座 （cis-eQTL） 影响。然而，复杂的连锁不平衡和相关表达阻碍了阐明遗传变异赋予潜在 CRC 风险的机制。目的 采用跨学科方法了解 11q23.1 位点的变异如何赋予 CRC 风险。设计 我们采用 RNA 测序、单细胞 RNA 测序、染色质免疫沉淀测序和单细胞 ATAC 测序数据分析来识别、优先排序和表征导致 CRC 风险的基因。我们使用小鼠模型进一步验证了这些发现，并证明了在人结肠粘膜中的平行效应。结果我们将 rs3087967 确定为 11q23.1 的主要 eQTL 变体，与 CRC 风险共定位。此外，rs3087967 影响 21 个远距离基因的表达，从而充当高度富集簇状细胞标志物的基因集的反式 eQTL 枢纽。表观基因组分析表明 POU2AF2 通过 POU2F3 相关基因组调控来控制簇状细胞特异性转基因。免疫荧光证实 rs3087967 风险基因型 （T） 与人结肠中的簇状细胞缺陷有关。CRISPR 介导的小鼠种系中 11q23.1 风险位点基因的缺失加剧了 ApcMin/+ 小鼠表型，特别是消除了 Pou2af2 表达。结论 我们证明 rs3087967 的基因型通过对 POU2AF2 的误调来控制基因组合。POU2AF2 是 Tuft 细胞的主要转录激活剂，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。与研究相关的所有数据都包含在文章中或作为补充信息上传。那。