Genes regulated by BP Noncoding SNPs in Relevant Cells

相关细胞中BP非编码SNPs调控的基因

• 批准号: 10667380
• 负责人: MINGYU LIANG
• 金额: $ 67.6万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667380
• 关键词: Binding Sites; Bioinformatics; Blood Pressure; Cell Differentiation process; Cell Line; Cell Reprogramming; Cells; Characteristics; Chromatin; Code; Complex; DNA; Data; Distal; Distant; Engineering; Epigenetic Process; Exhibits; Female; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genotype-Tissue Expression Project; Goals; Haplotypes; Human; Individual; Limb structure; Linkage Disequilibrium; Methods; Minor; Phenotype; Physiological; Physiology; Proteins; Protocols documentation; Proximal Kidney Tubules; Publishing; Quantitative Trait Loci; Series; Single Nucleotide Polymorphism; Testing; Thick; Tissues; Untranslated RNA; Vascular Endothelium; Vascular Smooth Muscle; blood pressure regulation; cell type; differential expression; epigenomics; genome editing; genomic locus; induced pluripotent stem cell; interest; male; programs; promoter; trait; transcriptome sequencing

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.

项目1项目概要 绝大多数单核苷酸多态性（SNP）与复杂的人类特征相关，包括 血压（BP）位于DNA的非编码区。这些非编码单核苷酸多态性，尤其是那些 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影响BP 表情表达数量性状基因座（eQTL）研究开始能够鉴定 非编码SNPs与基因表达之间的关联。 然而，很少有研究超越了协会，以检查BP的功能影响， 相关的非编码SNPs基因表达。这些研究必须克服大量的 挑战首先，BP相关的非编码SNPs可以调节远端蛋白编码基因的表达， 基因通过染色质折叠或非编码RNA，这意味着人们不能假设蛋白质编码 SNP调控的基因是顺序上最接近SNP的基因。第二，结果 eQTL和其他研究表明非编码SNP对基因表达的影响通常是细胞类型特异性的。 在本PPG的项目1中，我们开发了几种方法和途径来克服这些问题。 挑战，并测试BP相关的非编码SNP调节 这些基因在生理上对血压调节很重要。项目1中的所有三个目标都是 确定BP相关非编码SNP对BP相关细胞类型中基因表达的影响。每个 目的将集中在一组LD（连锁不平衡）区域位于远离任何蛋白质编码基因和一个 具体假设。将在本PPG的项目2和项目3中检验每个假设的机制方面。 项目1的可行性得到了一系列广泛的准备和初步研究的支持。 这个PPG提案的总体目标是鉴定由人类BP相关基因调控的基因。 非编码SNPs，检查潜在的机制，并调查其对BP的影响。项目1 侧重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相结合。项目1将依赖核心B进行广泛的RNA-seq分析。