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

• 批准号: 8913340
• 负责人: Manolis Kellis
• 金额: $ 23.42万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-02 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913340
• 关键词: Address; Adipose tissue; Affect; Alleles; Atlases; Behavioral; Biology; Brain; Brain region; Cerebellum; Chromatin; Cognitive; Complement; Complex; DNA Methylation; DNA Sequence; Data Set; Diabetes Mellitus; Disease; Enhancers; Epigenetic Process; Event; Functional RNA; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; 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; Variant; Whole Blood; Work; addiction; base; bisulfite; cell type; chromatin immunoprecipitation; chromatin modification; epigenomics; frontal lobe; genetic variant; genome wide association study; genome-wide; histone modification; human disease; human tissue; methylome; neuropsychiatry; promoter; sample collection; trait

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）正在扩大初级组织样本的可用性，用于研究遗传变异对个体和组织中基因表达的影响。然而，基因表达水平的个体间差异往往是由多个变异的共同作用造成的，每个变异都可能以复杂的方式影响不同调控区域的活性，并且还整合了复杂的转录后事件。因此，为了直接评估序列变异对调控元件的影响，我们建议对储存的GTEx生物标本进行系统的表观遗传修饰，以加强对GTEx联盟现有和计划的基因表达变异的分析。目的1。我们将使用全基因组亚硫酸盐测序（WGBS）来分析8个GTEx组织中20个个体基因组中所有28M CpGs的DNA甲基化水平。我们将使用这些来识别不同细胞类型和个体之间的可变甲基化区域（VMRs），评估eQTL snp对邻近CpGs 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个个体的DNA甲基化水平