Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells

Chun Su,Michelle E Leonard,Prabhat Sharma,Neil Romberg,Andrew D Wells,Sumei Lu,Matthew E Johnson,Annabel Torres,Elisabetta Manduchi,Rajan M Thomas,Struan F A Grant,Alessandra Chesi,Parul Mehra,Kenyaita M Hodge,Carole Le Coz,James Pippin

doi:10.1038/s41467-020-17089-5

Chun Su, Michelle E Leonard + Show 14 more

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https://doi.org/10.1038/s41467-020-17089-5

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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.

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Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues
As a step toward defining the diseaseassociated regulatory architecture of SLE, we focused on human TFH cells, which are required for the production of pathogenic antibodies by autoreactive B cells[4]
While open chromatin regions (OCR) in general are enriched for active chromatin marks[10,12], we find that iOCR are enriched up to 14-fold more for enhancer signatures compared to OCR not contacting a promoter (Fisher test p < 2 × 10−16, Fig. 4b and Supplementary Fig. 4b)

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Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. TFH differentiate from naive CD4+ T cells in the lymph nodes, spleen, and tonsil, where they license B cells to produce high affinity protective or pathogenic antibodies[5,6] Given their central role in regulation of humoral immune responses, genetic susceptibility to SLE is highly likely to manifest functionally in TFH. We conduct a genome-wide, promoter-focused Capture-C analysis of chromatin contacts at ~42,000 annotated human genes at ~270 bp resolution to map these variants to the genes they likely regulate This approach, which we used recently to identify new effector genes at bone mineral density loci[9], only requires three samples to make valid interaction calls, and does not require material from SLE patients or genotyped individuals. We experimentally verify roles for two kinases implicated by this variant-to-gene mapping approach in TFH differentiation and function, identifying potential drug targets for SLE and other antibody-mediated diseases

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