Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells
| Autor: | Michelle E. Leonard, Carole Le Coz, Annabel Torres, Struan F.A. Grant, Rajan M. Thomas, Chun Su, Kenyaita M. Hodge, Elisabetta Manduchi, Neil Romberg, Alessandra Chesi, Matthew E. Johnson, Andrew D. Wells, Sumei Lu, Parul Mehra, Prabhat K. Sharma, James A. Pippin |
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| Rok vydání: | 2020 |
| Předmět: |
Epigenomics
0301 basic medicine General Physics and Astronomy Genome-wide association study Jurkat Cells 0302 clinical medicine Genome editing immune system diseases Lupus Erythematosus Systemic Promoter Regions Genetic lcsh:Science skin and connective tissue diseases Chromosome conformation capture-based methods Cells Cultured Genetics Multidisciplinary Systemic lupus erythematosus Effector Chromosome Mapping Functional genomics T-Lymphocytes Helper-Inducer BCL6 medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-6 RNA Interference Receptors CXCR5 Science Protein Serine-Threonine Kinases Biology Polymorphism Single Nucleotide Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Chromatin analysis medicine Humans Genetic Predisposition to Disease Gene B cell Autoantibodies Gene Expression Profiling General Chemistry medicine.disease Gene regulation 030104 developmental biology lcsh:Q Human genome 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-17089-5 |
| Popis: | Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE ‘variant-to-gene’ maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome. T cells are a major cell type involved in systemic lupus erythematosus (SLE). Here, the authors use promoter capture-C and ATAC-seq in human follicular T helper cells to identify SLE genes distant from GWAS loci (via 3D interaction) and validate the function of key regulatory elements and genes in vitro. |
| Databáze: | OpenAIRE |
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