Systematic fine-mapping and functional studies of prostate cancer risk variants [ChIP-seq]

To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants in gene regulatory regions remain elusive. Identification of causal variants and their targets from association signals relevant to prostate cancer is complicated by high linkage disequilibrium and limited availability of functional genomics data for specific tissue/cell types. Here, we integrated statistical fine-mapping and functional annotation from prostate-specific epigenomic profiles, high resolution 3D genome features, and quantitative trait loci data to distinguish causal variants from associations and identify target genes they regulate. Our fine-mapping analysis yielded 1,892 likely causal variants, and multiscale functional annotation linked them to 406 target genes. We prioritized rs10486567, located in an enhancer, as a genome-wide top-ranked SNP and predicted HOTTIP as its target. Deletion of the rs10486567-associated enhancer in prostate cancer cells decreased their capacity for invasive migration. HOTTIP overexpression in an enhancer-KO cell line rescued defective invasive migration. Furthermore, we found that rs10486567 regulates HOTTIP through allele-specific long- range chromatin interaction. histone modifications of 22Rv1

截至目前，全基因组关联研究（genome-wide association studies, GWAS）已发现超过200个与前列腺癌相关的遗传风险位点，但基因调控区域内真正的致病变异仍未被探明。从与前列腺癌相关的关联信号中识别致病变异及其靶基因，受限于高连锁不平衡（linkage disequilibrium）以及特定组织/细胞类型功能基因组学数据的可获得性不足。本研究整合了前列腺特异性表观基因组谱、高分辨率三维基因组特征以及数量性状位点（quantitative trait loci）数据中的统计精细定位结果与功能注释信息，以区分关联信号中的致病变异并鉴定其调控的靶基因。本次精细定位分析共鉴定出1892个潜在致病变异，多尺度功能注释将这些变异与406个靶基因建立关联。本研究将位于增强子（enhancer）区域的rs10486567列为全基因组排名最高的单核苷酸多态性（single nucleotide polymorphism, SNP），并预测HOTTIP为其靶基因。在前列腺癌细胞中敲除rs10486567相关的增强子区域，会降低细胞的侵袭迁移能力。在增强子敲除的细胞系中过表达HOTTIP，可挽救受损的侵袭迁移表型。此外，本研究还发现rs10486567通过等位基因特异性长距离染色质相互作用调控HOTTIP的表达。22Rv1细胞的组蛋白修饰（histone modifications）