Identification and characterization of noncoding mutations causing autoinflammatory diseases

点击翻译按钮获取中文摘要

Autoinflammatory diseases, also called periodic fever syndromes, are defined by a group of monogenic or complex genetic disorders characterized by seemingly unprovoked episodes of inflammation in the absence of high levels of auto-antibodies or antigen-specific T cells. Genome-wide association studies (GWAS) and whole genome sequencing (WGS) were successfully applied to significantly associate a wide range of single nucleotide polymorphisms (SNPs) to autoinflammatory diseases. Interestingly, only approximately 10% of the disease-associated variants identified by GWAS actually fall into gene coding regions, while more than 90% coincide with noncoding and thus potentially regulatory regions of the genome. The goal of the prospective study is to use GWAS and WGS data in combination with public genomic and epigenomic datasets to identify autoinflammatory disease-associated SNPs that are located within cell-type specific enhancers. The candidate enhancers are then confirmed through structural and functional assays in innate immune cells such macrophages or as dendritic cells. Additionally, CRISPR/Cas9 technology will be used to either delete the complete enhancer fragment or to introduce a specific SNP into the genome of dendritic cells and zebrafish, a well established animal model to study defects of the immune system. Subsequently, transcriptome analyses provide information of candidate genes regulated through the modified enhancers. The described study will help to understand the significance of enhancers on human immunobiology and to gain new mechanistic insights into the role of enhancers and the effect of SNPs within these enhancers for manifestation and development of monogenic and complex autoinflammatory diseases.