Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA, USA.
Department of Pathology, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA, USA.
Nat Commun. 2020 Jul 3;11(1):3294. doi: 10.1038/s41467-020-17089-5.
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.
系统性红斑狼疮（SLE）是由自身反应性抗体介导的，这些抗体可损伤多种组织。全基因组关联研究（GWAS）将 60 多个位点与 SLE 风险相关联，但因果变异和效应基因在很大程度上尚不清楚。我们在人类滤泡辅助 T 细胞（TFH）中生成了 SLE 变体可及性和基因连通性的高分辨率空间图谱，TFH 是一种细胞类型，是产生抗核抗体所必需的，这些抗核抗体是 SLE 的特征。在鉴定的~400 个潜在调节变异中，90%的变异与 1D 基因组序列中远距离的基因具有空间邻近性，包括通过基因组编辑证实可调节经典 TFH 基因 BCL6 和 CXCR5 的变异。SLE 的“变体-基因”图谱还涉及到一些在 TFH/SLE 疾病生物学中没有已知作用的基因，包括激酶 HIPK1 和 MINK1。在 TFH 中靶向这些激酶可抑制 IL-21 的产生，IL-21 是一种对类别转换 B 细胞抗体至关重要的细胞因子。这些研究为人类基因组中与 SLE 相关的调节结构提供了机制上的见解。
