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Epigenome-Guided Causal Variant Discovery and Mechanisms

表观基因组引导的因果变异发现和机制

基本信息

批准号：
10408699
负责人：
Patrick M Gaffney
金额：
$ 64.18万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-06 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408699
关键词：
3-Dimensional Address Agonist Alleles Allelic Imbalance Antigen-Antibody Complex Antigens Autoantibodies Autoantigens Autoimmune Diseases Automobile Driving B-Cell Antigen Receptor B-Lymphocytes Bioinformatics Biological Assay Blood donor CD40 Ligand Cell Line Cell physiology Cells ChIP-seq Chromatin Chromatin Loop Complement Complex Control Groups DNA Resequencing Data Disease Disease Progression Enhancers Epigenetic Process Exhibits Exposure to Gene Expression Gene Structure Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genetic Research Genetic Risk Genetic Translation Genomic Segment Genotype Haplotypes Histones Human Human Herpesvirus 4 Imiquimod Immune System Diseases Immune Tolerance Immunoglobulin M Inflammatory Influentials Interferons Knowledge Laboratories Lead Linkage Disequilibrium Maps Measures Messenger RNA Methods Molecular Onset of illness Organ Pathogenesis Pathway interactions Phenotype Positioning Attribute Precision Medicine Initiative Process Production Publishing Quantitative Trait Loci Regulation Reporter Reproducibility Research Resources Rest Risk Sampling Scanning Self Tolerance Stimulus Systemic Lupus Erythematosus TLR7 gene Technology Testing Transcriptional Regulation Translating Variant case control causal variant chromatin modification chromosome conformation capture clinically actionable crosslink disorder risk epigenome experimental study gene expression variation gene network genetic variant genome wide association study genome-wide innovation novel strategies promoter public database response risk variant transcriptome sequencing

项目摘要

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by dysregulated interferon responses and loss of self-tolerance to cellular antigens, which result in inflammatory processes that ultimately lead to systemic end-organ damage. Despite decades of research, the underlying mechanisms driving the pathogenesis of SLE remain incompletely understood. Genome-wide association studies (GWAS) have identified over 100 SLE risk haplotypes carrying hundreds of SNPs with unknown functional importance in disease onset and progression. Distinguishing causal from non-causal SNPs, and thus translating genetic knowledge into actionable clinical knowledge has been a laborious, inefficient, and resource-intensive task. Our laboratory has developed a new approach to expedite the causal variant discovery process where we use the epigenome to identify likely causal variants on risk haplotypes. We do this by identifying epigenetic footprints of allelic imbalance at SNPs (“hQTLs”) in poised and active enhancers measured by ChIP- sequencing. Our approach is able to identify causal variants in the context of linkage disequilibrium and provides a priori evidence that the putative causal variant is functional by identifying allelic imbalance in the magnitude of histone marks. We also use 3D chromatin topology data to construct a molecular wiring diagram of interacting enhancers and promoters that contain hQTLs. Since these data leverage the epigenome distinct profiles in specific cells and cell states provide important contextual information about what cellular processes the epiQTL is most important in regulating. This resubmission of R01 AR073606 aims to 1) use an epigenome-guided approach to identify resting and stimulus-dependent hQTLs from primary B cells; 2) validate and confirm the allele-specific transcriptional regulation attributed to hQTLs using an orthogonal massively parallel reporter assay; and 3) determine how hQTLs modify gene expression and 3D chromatin organization of genes contained within regulatory networks of hQTLs using multiplex quantitative PCR and chromatin conformation capture (3C). We believe this project positions us at the leading edge of causal variant identification and risk haplotype functional characterization and will contribute to a better understanding of the connection between genotype and phenotype for human SLE and related autoimmune diseases.

项目总结