Genes regulated by BP Noncoding SNPs in Relevant Cells

项目1项目总结 绝大多数单核苷酸多态(SNPs)与复杂的人类特征相关，包括 血压，位于DNA的非编码区。这些非编码SNP，特别是那些 位于远离蛋白质编码基因的单倍型区域，很可能通过调节基因来影响BP 表情。表达数量性状基因座(EQTL)研究开始使人们能够识别 非编码SNPs与基因表达之间的关联。 然而，很少有研究超越关联来研究BP的功能效应。 与基因表达相关的非编码SNPs。这样的研究必须克服大量的 挑战。首先，BP相关的非编码SNPs可以调节远端编码蛋白质的表达 基因通过染色质折叠或非编码RNA，这意味着人们不能假设编码蛋白质的 受SNPs调控的基因是那些顺序上最接近SNPs的基因。第二，结果来自 EQTL和其他研究表明，非编码SNPs对基因表达的影响通常是细胞类型特有的。 在这个PPG的项目1中，我们开发了几个克服这些问题的途径和方法 挑战并检验与BP相关的非编码SNPs调控 对血压调节具有重要生理意义的基因。项目1中的所有三个目标都有共同的目标 确定BP相关非编码SNPs对BP相关细胞类型中基因表达的影响。每个人 AIM将专注于远离任何蛋白质编码基因的一组LD(连锁不平衡)区域和一个 具体的假设。每个假设的机械方面将在本PPG的项目2和3中进行测试。 项目1的可行性得到了广泛的一系列筹备和初步研究的支持。 这项PPG提案的总体目标是识别受人类BP相关基因调控的基因 对SNP进行非编码，研究其潜在机制，并研究其对BP的影响。项目1 专注于总体目标的第一部分，并将通过广泛的 与项目2和项目3整合。项目1将依赖核心B进行广泛的RNA-seq分析。

PROJECT 1 PROJECT SUMMARY The vast majority of single nucleotide polymorphisms (SNPs) associated with complex human traits, including blood pressure (BP), are located in noncoding regions of DNA. These noncoding SNPs, especially the ones located in haplotype regions far from protein-coding genes, most likely influence BP by regulating gene expression. Expression quantitative trait locus (eQTL) studies are beginning to enable the identification of associations between noncoding SNPs and gene expression. However, very few studies have gone beyond associations to examine the functional effect of BP- associated noncoding SNPs on gene expression. Such studies would have to overcome substantial challenges. First, BP-associated noncoding SNPs could regulate the expression of distant protein-coding genes through chromatin folding or noncoding RNA, which means one cannot assume that the protein-coding genes that the SNPs regulate are the ones that are sequentially closest to the SNPs. Second, results from eQTL and other studies indicate the effect of noncoding SNPs on gene expression is often cell type-specific. In Project 1 of this PPG, we have developed several approaches and methods to overcome these challenges and to test the overall hypothesis that BP-associated noncoding SNPs regulate the expression of genes that are physiologically important to BP regulation. All three aims in Project 1 share the goal of identifying the effect of BP-associated noncoding SNPs on gene expression in BP-relevant cell types. Each aim will focus on a group of LD (linkage disequilibrium) regions located far from any protein-coding gene and a specific hypothesis. The mechanistic aspect of each hypothesis will be tested in Projects 2 and 3 of this PPG. The feasibility of Project 1 is supported by an extensive series of preparatory and preliminary studies. The overall goal of this PPG proposal is to identify genes regulated by human BP-associated noncoding SNPs, examining the underlying mechanisms, and investigating their influence on BP. Project 1 focuses on the first part of the overall goal and will contribute to the goal of the program through extensive integration with Projects 2 and 3. Project 1 will rely on Core B for extensive RNA-seq analysis.