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Epigenomic variation atlas across human tissues and individuals in GTEx

GTEx 中人体组织和个体的表观基因组变异图谱

基本信息

批准号：
9057603
负责人：
Manolis Kellis
金额：
$ 10万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2014-06-02 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057603
关键词：
Address Adipose tissue Affect Alleles Atlases Behavioral Biology Brain Brain region Cerebellum ChIP-seq Chromatin Cognitive Complement Complex DNA Methylation DNA Sequence Data Set Diabetes Mellitus Disease Enhancers Epigenetic Process Event Gene Expression Gene Expression Profile Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Variation Genome Genomic Segment Genotype Genotype-Tissue Expression Project Health Heart Heart Diseases Hippocampus (Brain)Histone Acetylation Human Human Genome Hybrids Hypothalamic structure Immunoglobulin Variable Region Individual Libraries Lung Malignant Neoplasms Maps Mediating Methylation Modeling Modification Molecular Nature Nucleic Acid Regulatory Sequences Obesity Pattern Promoter Regions QTL Genes Quality Control Quantitative Trait Loci Reading Regulator Genes Regulatory Element Resources Role Sampling Sampling Studies Sensitivity and Specificity Skeletal Muscle Skin Specificity Stress Substantia nigra structure Tars Thyroid Gland Tissue Sample Tissues Untranslated RNA Variant Whole Blood Work addiction base bisulfite sequencing cell type chromatin modification epigenomics frontal lobe genetic variant genome wide association study genome-wide histone modification human disease human tissue inter-individual variation methylation biomarker methylation pattern methylome neuropsychiatric disorder neuropsychiatry promoter sample collection trait whole genome

项目摘要

DESCRIPTION (provided by applicant): The Genotype-Tissue Expression project (GTEx) is expanding the availability of primary tissue samples for studying the impact of genetic variation on gene expression across individuals and tissues. However, inter-individual variation in gene expression level can often result from the combined effects of multiple variants, each of which may affect the activity of different regulatory regions in complex ways, and also integrate complex post-transcriptional events. Thus, to directly assess the effect of sequence variants on regulatory elements, we propose to systematic profile epigenetic modifications on stored GTEx biospecimens to enhance the analysis of gene expression variation already available and planned by the GTEx consortium. Aim 1. We will use whole-genome bisulfite sequencing (WGBS) to profile DNA methylation levels for all 28M CpGs in the genome of 20 individuals in 8 GTEx tissues. We will use these to identify variable methylated regions (VMRs) across cell types and across individuals, to evaluate the effects of eQTL SNPs on DNA methylation levels of neighboring CpGs, and to recognize allele-specific methylation (ASM) regions and their tissue specificity. Aim 2. We will systematically profile DNA methylation levels across 250 individuals in the same 8 tissues using hybrid-selection bisulfite sequencing (HSBS) for a subset of 2M regions selected within enhancer-associated, eQTL-associated, and inter-individual variable regions. We will use these to predict methylation quantitative trait loci (meQTLs) in each tissue, relate these to GTEx expression QTLs (eQTLs) for the same tissues to provide mechanistic hypotheses for inter- individual gene expression variation, and to discover meQTLs for genes where no single eQTL is significant. Aim 3. We will use chromatin immunoprecipitation sequencing (ChIP-Seq) to profile enhancer- and promoter-associated histone modification H3K27ac in 6 GTEx brain samples across 100 individuals, to recognize genotype-associated enhancer regions and enhQTLs. We will relate these to eQTLs in the same tissues and meQTLs discovered using HSBS on enhancer-proximal and eQTL proximal CpGs to generate mechanistic models for regulatory changes associated with genotype variation. We will work closely with the GTEx Analysis Consortium to integrate GTEx eQTLs with our predicted meQTLs, ASM regions, and enhQTLs to relate regulatory region variation to gene expression variation and to genome-wide association studies to understand the role of sequence variation in tissue-specific gene regulation, gene expression, and human disease.

描述（由申请人提供）：基因型组织表达项目（GTEx）正在扩大原始组织样本的可用性，以研究遗传变异对个体和组织基因表达的影响。然而，个体间基因表达水平的变异往往是多种变异共同作用的结果，每种变异都可能以复杂的方式影响不同调控区域的活性，并整合复杂的转录后事件。因此，为了直接评估序列变异对调控元件的影响，我们建议对存储的 GTEx 生物样本进行系统的表观遗传修饰分析，以增强对 GTEx 联盟已经可用和计划的基因表达变异的分析。目标 1. 我们将使用全基因组亚硫酸氢盐测序 (WGBS) 来分析 8 个 GTEx 组织中 20 个个体的基因组中所有 28M CpG 的 DNA 甲基化水平。我们将使用这些来识别跨细胞类型和个体的可变甲基化区域 (VMR)，评估 eQTL SNP 对邻近 CpG 的 DNA 甲基化水平的影响，并识别等位基因特异性甲基化 (ASM) 区域及其组织特异性。目标 2. 我们将系统地分析 250 名个体的 DNA 甲基化水平使用混合选择亚硫酸氢盐测序 (HSBS) 对相同的 8 个组织进行增强子相关、eQTL 相关和个体间可变区中选择的 2M 区域子集的分析。我们将使用这些来预测每个组织中的甲基化数量性状位点（meQTL），将它们与相同组织的 GTEx 表达 QTL（eQTL）联系起来，为个体间基因表达变异提供机制假设，并发现没有单个 eQTL 显着的基因的 meQTL。目标 3. 我们将使用染色质免疫沉淀测序 (ChIP-Seq) 来分析 100 名个体的 6 个 GTEx 大脑样本中增强子和启动子相关的组蛋白修饰 H3K27ac，以识别基因型相关的增强子区域和 enhQTL。我们将这些与相同组织中的 eQTL 和使用 HSBS 在增强子近端和 eQTL 近端 CpG 上发现的 meQTL 联系起来，以生成与基因型变异相关的调控变化的机制模型。我们将与 GTEx 分析联盟密切合作，将 GTEx eQTL 与我们预测的 meQTL、ASM 区域和 enhQTL 整合，将调控区域变异与基因表达变异以及全基因组关联研究联系起来，以了解序列变异在组织特异性基因调控、基因表达和人类疾病中的作用。