Research Resources: Epigenomic and Transcriptomic Profiles of Human Immune Cells

研究资源：人类免疫细胞的表观基因组和转录组图谱

基本信息

批准号：
8740928
负责人：
MITCHELL KRONENBERG
金额：
$ 89.92万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8740928
关键词：
Acetylation Affect Alleles Applications Grants Asthma Autoimmune Diseases Autoimmune Process Binding Sites Bioinformatics Borates Cardiovascular Diseases Cardiovascular system Cataloging Catalogs Cells Communicable Diseases Communities Computer Analysis DNA DNA Sequence Data Data Set Databases Dengue Diabetes Mellitus Disease Disease Outcome Disease model Disease susceptibility Elements Enhancers Functional RNA Gene Expression Gene Targeting Genes Genetic Transcription Genetic Variation Genome Genomics Genotype Goals Haplotypes Histones Human Immune Immune System Diseases Immune system Immunologist Immunology Inflammatory Institutes Leukapheresis Link Location Lysine Malaria Molecular Molecular Analysis Molecular Profiling Monoclonal Antibody R24 Nucleic Acid Regulatory Sequences Online Systems Paper Pathway interactions Population Predisposition RNA Sequences Regulatory Element Research Resources Role Sampling Scientist Single Nucleotide Polymorphism Site Specificity Study Subject Testing Transcription factor genes Tuberculosis Variant base cell type chromatin immunoprecipitation design epigenomics genetic variant genome wide association study genome-wide histone modification human disease human subject new therapeutic target next generation sequencing tool transcription factor transcriptome sequencing transcriptomics web site

项目摘要

DESCRIPTION (provided by applicant): Genome-wide association studies (GWAS) have identified genetic variants (often single-nucleotide polymorphisms, SNPs) associated with increased susceptibility to many human diseases. The vast majority of these variants are located in non-coding genomic regions, and so are thought to influence disease outcome by perturbing the functions of cis-regulatory DNA elements that control gene expression on the same allele. To understand the role of common genetic variations in human disease, we propose here to perform epigenomic and transcriptomic analyses of 13 purified circulating immune cell types from healthy human subjects. Aim 1: For each immune cell type from each donor, we will determine the genome-wide locations of H3K4me2 and H3K27Ac, two histone modifications associated with functional enhancers; we will also obtain the transcriptional profiles of the cells as well as genotype and whole-genome haplotype information. This will allow us to determine, for each human cell type, the gene expression profiles as well as the strength and cell type-specificity of cis-regulatory elements. Aim 2: We will identify cis-regulatoy elements that harbor disease- associated variants, predict if they disrupt transcription factor binding sites, and use data from heterozygous subjects to determine if allele-specific differences in cis-regulatory activity are linked to corresponding changes in gene expression on the cis allele. This will allow us to establish a computational pipeline that predicts, for each set of disease-associated genetic variations, which cis-regulatory elements, transcription factors, genes, immune cell types and molecular pathways are most likely to be disrupted. Aim 3: We will make our experimental results and analysis tools available on a dedicated website that will be designed and optimized to provide immunologists with intuitive interfaces that maximize the ability to answer research questions without requiring advanced bioinformatics expertise. RELEVANCE: For many human diseases, large-scale genomic studies have identified common genetic variants that occur more frequently in people with cardiovascular, autoimmune, inflammatory and infectious diseases, diabetes and asthma than in those without these diseases. Here we propose to understand how these variants cause susceptibility to disease, focusing on diseases related to the immune system, and use this information to find novel therapeutic targets for these diseases.

描述（由申请人提供）：全基因组关联研究（GWAS）已经鉴定出与增加对许多人类疾病的易感性相关的遗传变异（通常是单核苷酸多态性，SNP）。这些变体中的绝大多数都位于非编码基因组区域，因此被认为通过扰动顺式调节性DNA元件的功能来影响疾病的结果，从而控制基因表达在同一等位基因上。为了了解常见遗传变异在人类疾病中的作用，我们在这里建议对健康人类受试者的13种纯化的循环免疫细胞类型进行表观基因组和转录组分析。 AIM 1：对于每个供体的每种免疫细胞类型，我们将确定H3K4ME2和H3K27AC的全基因组位置，两种与功能增强子相关的组蛋白修饰。我们还将获得细胞的转录谱以及基因型和全基因组单倍型信息。这将使我们能够确定每种人细胞类型的基因表达谱以及顺式调节元件的强度和细胞类型特异性。 AIM 2：我们将确定具有疾病相关变体的CIS-Regulatoy元素，预测它们是否破坏转录因子结合位点，并使用杂合受试者的数据来确定顺式调节活性的等位基因特异性差异是否与CISERELERELELERELERELERELERELERELION基因表达的相应变化有关。这将使我们能够建立一条计算管道，以预测每组与疾病相关的遗传变异，这些遗传变异最有可能中断，这些元素，转录因子，基因，免疫细胞类型和分子途径最有可能被破坏。 AIM 3：我们将在专用网站上提供实验结果和分析工具，该网站将被设计和优化，以为免疫学家提供直观的接口，从而最大程度地提高回答研究问题的能力，而无需高级生物信息学专业知识。相关性：对于许多人类疾病，大规模的基因组研究已经确定了常见的遗传变异，这些遗传变异体发生在心血管，自身免疫，炎症和传染病，糖尿病和哮喘的患者中比没有这些疾病的患者更频繁地发生。在这里，我们建议了解这些变体如何引起对疾病的敏感性，专注于与免疫系统有关的疾病，并使用此信息来找到这些疾病的新型治疗靶标。