Resolving molecular mechanisms of autoimmune disease in primary CD4 T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): synthetic construct Homo sapiens
PROVIDER: GSE135925 | GEO | 2020/03/21
REPOSITORIES: GEO
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Project description:Numerous genomic loci have been implicated in autoimmune disorders, but attempts to identify causal variants, and thereby disease mechanisms, have been hampered by strong linkage disequilibrium – leaving most loci unresolved and the potential of GWAS unfulfilled. To overcome this, we developed a massively-parallel reporter assay for use in primary CD4 T-cells, a key effector of many autoimmune diseases, and sought to resolve potential causal variants via their functional effects. We identified a specific functional variant at a pleiotropic locus that has been associated with multiple immune mediated diseases, and confirmed that this modulated expression by disrupting an NFKB binding site. To determine the resulting effect on enhancer activity we performed H3K27ac ChIP in stimulated CD4 T cells from 3 major allele homozygotes and 3 minor allele homozygotes at rs6927172.
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Project description:Genetic sharing is extensively observed for many autoimmune diseases, but the causal variants and their underlying molecular mechanisms remain largely unknown. Through systematic investigation of known autoimmune disease pleiotropic loci, we found that most of these genetic effects are transmitted from regulatory code and colocalize with hematopoietic lineage-specific expression quantitative trait loci. We used an evidence-based strategy to functionally prioritize known pleiotropic variants and identify their target genes. A top-ranked pleiotropic variant, rs4728142, yielded many lines of evidence as being causal, and regulates IRF5 transcript expression. Mechanistically, the rs4728142-containing region interacts with the IRF5 downstream alternative promoter in an allele-specific manner and orchestrates its upstream enhancer to regulate IRF5 alternative promoter usage through chromatin looping. A putative structural regulator, ZBTB3, mediates the allele-specific chromatin looping to promote IRF5 short transcript expression at the rs4728142 risk allele, resulting in IRF5 overactivation and M1 macrophage polarization. Together, our findings establish a causal mechanism between the regulatory variant and fine-scale molecular phenotype underlying the dysfunction of pleiotropic genes in human autoimmunity.
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