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Systematic Mapping of the Functional Common Noncoding Variants in the TNFAIP3 Locus

TNFAIP3 基因座功能性常见非编码变异的系统作图

基本信息

批准号：
9258074
负责人：
John Philip Ray
金额：
$ 5.71万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258074
关键词：
A20 protein Affect Alleles Animal Disease Models Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Binding Biochemical Biological Assay CRISPR/Cas technology Cells Chromatin Complex Data Diagnostic Factor Disease Disease model Enhancers Environment Epigenetic Process Future Gene Expression Gene Expression Profile Genes Genetic Genetic Engineering Genetic Predisposition to Disease Genetic Variation Genome Genome engineering Genomics Goals Haplotypes Heritability Human Human Genetics Immune Knowledge Learning Linkage Disequilibrium Maps Methods Mus Mutation Nature Nucleic Acid Regulatory Sequences Pathogenesis Pathogenicity Patients Population Protein Isoforms RNA Splicing Regulation Regulator Genes Reporter Research Risk Site Syndrome Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic United States Variant Woman Work base cell type epigenetic variation genetic variant genome wide association study genome-wide genotyped patients histone modification improved in vivo insight monocyte mouse model new therapeutic target personalized medicine repaired trait transcription factor transcriptomics

项目摘要

Project Summary/Abstract The mechanisms for induction of autoimmunity remain enigmatic, in part due to the unconfirmed activity of many autoimmune-associated noncoding common genetic variants. To dissect the specific mechanisms of how all common and disease-associated noncoding variation modulates gene expression, I propose to employ scalable assays in three cell types that will assess 2708 noncoding common variants for gene-modulatory function in an important autoimmune-associated locus containing the negative regulatory gene TNFAIP3/A20. One assay will test ~2700 variants for their effects on reporter expression pre- and post-stimulation. A second assay will evaluate ~43,000 systematic locus-wide deletions in the genome to determine regulatory regions (and potentially active variants within) in cell types. I will then map the active disease-associated variants from these assays to the open chromatin of autoimmune patient cell types to create a ranked list of those that putatively operate in disease. I will then determine the mechanism of action for these active, open chromatin localized variants through genetically engineering risk and non-risk alleles using CRISPR-Cas9 homology directed repair and performing biochemical assays. This method is scalable to study many loci in future work, which will contribute to our knowledge of disease gene networks, accurate animal disease models, and more efficacious therapeutics.

项目总结/文摘