Epigenomes and Epigenetic Mechanisms in BP-relevant Tissues

BP相关组织的表观基因组和表观遗传机制

• 批准号: 10667384
• 负责人: ANDREW S. GREENE
• 金额: $ 59.79万
• 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/10667384
• 关键词: ATAC-seq; Accounting; Base Pairing; Bioinformatics; Biopsy; Blood Pressure; Cardiovascular Diseases; Cell physiology; Cells; Chromatin; Chromatin Loop; Code; DNA; DNA Methylation; DNA Sequence; DNA analysis; DNA-Protein Interaction; Data; Data Analyses; Development; Engineering; Enhancers; Environment; Epigenetic Process; Event; Gene Expression; Genes; Genetic; Genome; Goals; Haplotypes; Heritability; Hi-C; Human; Human Genome; Hypertension; Individual; Kidney; Knowledge; Laboratories; Link; Maps; Mediating; Myocardial Ischemia; Nephrons; Pathway interactions; Phenotype; Physiological; Physiology; Program Research Project Grants; Proteins; Reagent; Research; Research Personnel; Resistance; Resolution; Risk Factors; Role; Single Nucleotide Polymorphism; Stroke; Testing; Tissues; Untranslated RNA; Validation; Variant; arteriole; blood pressure control; blood pressure regulation; cell type; data exchange; epigenetic regulation; epigenome; epigenomics; experimental study; genome editing; genome wide association study; genome-wide; human tissue; induced pluripotent stem cell; validation studies; whole genome

PROJECT 2 PROJECT SUMMARY Hypertension remains the most important risk factor for a wide variety of cardiovascular diseases accounting for approximately 54 percent of all strokes and 47 percent of all ischemic heart disease events globally. Despite the fact that we know there is a significant genetic component that determines the level of blood pressure (BP; estimates of heritability of BP range from 30-70%) we are far from understanding the myriad of genetic factors that account for BP variation in humans. One of the most significant challenges for understanding genetic control of BP is that the vast majority of BP-associated single nucleotide polymorphisms (SNPs) that have been identified in human genome wide association studies (GWAS) are located in noncoding regions of DNA. Many of the noncoding SNPs (ncSNPs) are in haplotype regions located thousands of base pairs away from any protein-coding gene making it nearly impossible to link the SNPs to a protein-coding gene or a physiological pathway that regulates BP based on sequence and our current knowledge of the mechanism of action for the SNPs. In this project we will focus on testing the specific hypothesis that many ncSNPs identified in GWAS impact the expression of BP relevant genes through epigenetic mechanisms. Epigenetics refers to stable changes in DNA function that are not directly due to changes in the sequence of DNA. Epigenomics refers to such changes when they occur across the entire genome. Therefore, we will use state- of-the-art epigenomic and epigenetic approaches to probe the epigenetic mechanisms by which individual ncSNPs impact the expression of genes associated with BP in human GWAS. Using nephron segments that we will micro-dissect from fresh human kidney and human resistance arterioles isolated from gluteal biopsies as well as related cell types that will be derived from human inducible pluripotent stem cells (iPSCs), we will create an epigenomic map of human BP related cells and tissues at an unprecedented tissue resolution. Using that map combined with our bioinformatic analysis of human GWAS SNP data and data from Project 1 in this PPG (effects of BP ncSNPs on gene expression) we will then test specific epigenetic mechanisms for individual SNPs. Finally, we will perform validation studies in which precision genome editing and targeted epigenetic analysis are utilized to determine if the hypothesized mechanisms are responsible for changes in gene expression in BP-relevant cell types. This project is highly collaborative with the other projects and cores in this Program Project Grant through the sharing of reagents (cells and tissues), transfer of data, and the intellectual environment of the investigators and their laboratories.

项目2项目摘要 高血压仍然是多种心血管疾病会计的最重要的风险因素 全球所有中风中约有54％和所有缺血性心脏病事件的47％。 尽管我们知道有一个重要的遗传成分决定了血液的水平 压力（BP； BP遗传力的估计范围为30-70％），我们远非了解无数 解释了人类BP变异的遗传因素。最重要的挑战之一 了解BP的遗传控制是绝大多数BP相关的单核苷酸多态性 （SNP）已在人类基因组广泛关联研究（GWAS）中鉴定出的（GWAS）位于非编码中 DNA区域。许多非编码SNP（NCSNP）都位于单倍型区域 远离任何蛋白质编码基因，几乎不可能将SNP连接到蛋白质编码基因 或根据序列调节BP的生理途径以及我们当前对机制的了解 SNP的动作。在这个项目中，我们将重点介绍许多NCSNP的具体假设 在GWA中鉴定出的通过表观遗传机制影响BP相关基因的表达。表观遗传学 是指DNA功能的稳定变化，这不是直接是由于DNA序列的变化而引起的。 表观基因组学是指在整个基因组中发生的这种变化。因此，我们将使用状态 - 探测个体的表观遗传机制的表观基因组和表观遗传学方法 NCSNP会影响人类GWA中与BP相关的基因的表达。使用肾单位段 我们将从从臀臀活检中分离出的新鲜人类肾脏和人类抗性小动脉中微脱落 以及将从人诱导的多能干细胞（IPSC）中得出的相关细胞类型，我们将 在前所未有的组织分辨率下创建与人BP相关细胞和组织的表观基因组图。 使用该地图与我们对人类GWAS SNP数据的生物信息学分析和项目1中的数据结合 然后，我们将测试特定的表观遗传机制的PPG（BP NCSNP对基因表达的影响） 单个SNP。最后，我们将进行验证研究，其中精确的基因组编辑和针对性 表观遗传分析用于确定假设的机制是否导致变化 BP相关细胞类型中的基因表达。该项目与其他项目和核心高度合作 在这个计划项目中，通过共享试剂（细胞和组织），数据传输以及 研究人员及其实验室的智力环境。