Promoter interactome-aided mapping of unexplored CVID genetic landscapes

未探索的 CVID 遗传景观的启动子相互作用组辅助绘图

• 批准号: 10640143
• 负责人: NEIL David ROMBERG
• 金额: $ 57.02万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640143
• 关键词: 3-Dimensional; ATAC-seq; Affinity; Antibodies; Architecture; Autoimmune Diseases; B-Lymphocytes; BLR1 gene; Blood specimen; CD19 gene; CD4 Positive T Lymphocytes; Cataloging; Catalogs; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cessation of life; Chromatin; Coculture Techniques; Code; Combinatorics; Common Variable Immunodeficiency; Communicable Diseases; Complement 3d Receptors; Copy Number Polymorphism; DNA; Data; Data Set; Disease; Environment; Epigenetic Process; Euchromatin; Fostering; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genome Mappings; Genomic Segment; Genotype; Goals; Grant; Helper-Inducer T-Lymphocyte; Homeostasis; Hyperplasia; Immunocompetent; Immunoglobulin Class Switching; Immunoglobulin D; Immunologic Deficiency Syndromes; Individual; Inherited; Investigation; Linkage Disequilibrium; Lymph Node Dissections; Lymphocyte; Lymphocyte Function; Lymphoid Tissue; Maps; Measures; Mendelian disorder; Methods; Pathogenesis; Pathology; Patients; Phenotype; Predisposition; Proteins; Proxy; Publishing; Quantitative Trait Loci; RNA library; Sampling; Sentinel; Single Nucleotide Polymorphism; Sorting; Spliced Genes; Structure; Structure of germinal center of lymph node; Symptoms; T-Lymphocyte; Technology; Testing; Tissues; Tonsil; Transcript; Transcriptional Regulation; Untranslated RNA; Validation; Variant; Work; cell type; chromosome conformation capture; clinically significant; common symptom; congenital immunodeficiency; exome; gene interaction; genetic variant; genetically modified cells; genome wide association study; genome-wide; innovation; interleukin-21; lymph node biopsy; lymph nodes; novel diagnostics; novel therapeutics; personalized medicine; programs; promoter; response; transcriptome; whole genome

PROJECT SUMMARY/ABSTRACT Common variable immunodeficiency (CVID) is a primary disease of germinal center (GC) dysfunction, yet most CVID mechanistic investigations have utilized patient blood samples, which do not contain bona fide GC cells. Similarly, genome-wide association studies (GWAS) of CVID patients have identified many disease-associated single nucleotide polymorphisms (SNPs), yet most lie in non-coding DNA and are of unclear relevance to disease pathogenesis. The long-range goal of the proposed work is to determine the full genetic basis of CVID. The objective of this grant is to determine which non-coding regions of DNA contribute to GC dysfunction. The working hypothesis is that CVID GWAS SNPs point to important non-coding genomic regions that interact with promoters of genes key to GC lymphocyte function. Further, genetic variation altering gene promoter interactions, or damage to these genes themselves, will lead to GC dysfunction and eventually the symptoms of CVID. Our rationale is that identifying gene promoter interactions critical to GC homeostasis will provide new diagnostic and therapeutic opportunities for patients suffering from diseases of GC dysfunction including, but not limited to, CVID. Our specific aims will test the following hypotheses: (Aim 1) CVID GWAS associated regions euchromatically interact with gene promoters in T follicular helper cells (Tfh) and/or follicular B cells (FO B cells); (Aim 2) these interactions influence gene expression; (Aim 3) non-coding variants altering gene expression or variants damaging coding genes are enriched in CVID patients and that rhese variants alter Tfh and FO B cell function. The contribution is significant because cataloguing the genes and gene promoter contacts vital to GC homeostasis/dysfunction will offer new disease discovery opportunities and provide new molecules to target with personalized therapies. The proposed work is innovative because we are reinterpreting published GWAS with a suite of interlocking genome-scale technologies capable of annotating individual SNPs with overlapping layers of cell type-specific epigenetic information including promoter contacts, chromatin availability and gene expression. Further, we are verifying our findings in CVID exomes and genomes, with genetically modified cell-lines, with patient lymph nodes and in co-cultures that recapitulate key transcriptional features of the GC environment.

项目总结/文摘