Prostate Cancer Risk Enhancers

 描述（由申请人提供）：这是对现有资助项目的竞争性更新的修订，以确定前列腺癌（PCa）风险增强剂及其靶基因。我们打算确定所有受新发现的增强子影响的靶基因，这些增强子在77个已知的PCa风险位点含有遗传变异。全基因组关联（GWAS）位点的主要“问题”是缺乏对风险等位基因功能的机制性理解。这由于绝大多数（>90%的PCa风险等位基因）存在于非编码DNA如增强子中的事实而加剧。因此，本申请旨在使用三种独立的方法系统地鉴定所有新鉴定的PCa风险增强剂的靶基因，在此在三种共同PI的支持下将其表述为三个特定目标。这三个目标是：eQTL（Coetzee）将SNP基因型与全基因组的基因表达水平联系起来，CRISPR（Farnham）原位编辑增强子（缺失和等位基因置换），将它们与基因表达联系起来，最后4C（Lu）通过染色质构象捕获将增强子与潜在的靶基因匹配。该计划的优势在于，通过所有三种方法鉴定的共同靶基因可能具有重要的功能。结果将阐明以前未预料到的风险机制，并为诊断和预防提供依据。

 DESCRIPTION (provided by applicant): This is a revision of a competitive renewal of an existing funded project to identify prostate cancer (PCa) risk enhancers and their target genes. We intend to identify all target genes affected by newly identified enhancers that contain genetic variation at 77 known PCa risk loci. The major `problem' of genome-wide association (GWAS) loci is the lack of mechanistic understanding of how risk alleles function. This is exacerbated by the fact that the vast majority (>90% of PCa risk alleles) resides in non-coding DNA such as enhancers. This application therefore intends to systematically identify target genes of all the newly identified PCa risk enhancers using three independent approaches, formulated here as three specific aims under the auspices of three co-PIs. The three aims are: eQTL (Coetzee) to link SNP genotypes with levels of gene expression genome-wide, CRISPRs (Farnham) to edit enhancers in situ (deletion and allelic replacement) linking them with gene expression and finally 4C (Lu) to match enhancers with potential target genes by chromatin conformation capture. The strength of this plan is that common target genes identified by all three approaches are likely to be functionally significant. Results will elucidate previously unanticipated risk mechanisms and will provide rationale for diagnosis and prevention.