Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Nat Genet. 2023 Dec;55(12):2200-2210. doi: 10.1038/s41588-023-01577-7. Epub 2023 Nov 30.
In autoimmune diseases such as rheumatoid arthritis, the immune system attacks the body's own cells. Developing a precise understanding of the cell states where noncoding autoimmune risk variants impart causal mechanisms is critical to developing curative therapies. Here, to identify noncoding regions with accessible chromatin that associate with cell-state-defining gene expression patterns, we leveraged multimodal single-nucleus RNA and assay for transposase-accessible chromatin (ATAC) sequencing data across 28,674 cells from the inflamed synovial tissue of 12 donors. Specifically, we used a multivariate Poisson model to predict peak accessibility from single-nucleus RNA sequencing principal components. For 14 autoimmune diseases, we discovered that cell-state-dependent ('dynamic') chromatin accessibility peaks in immune cell types were enriched for heritability, compared with cell-state-invariant ('cs-invariant') peaks. These dynamic peaks marked regulatory elements associated with T peripheral helper, regulatory T, dendritic and STAT1CXCL10 myeloid cell states. We argue that dynamic regulatory elements can help identify precise cell states enriched for disease-critical genetic variation.
在类风湿性关节炎等自身免疫性疾病中，免疫系统会攻击人体自身的细胞。深入了解非编码自身免疫风险变异赋予因果机制的细胞状态对于开发治愈性疗法至关重要。在这里，为了鉴定与细胞状态定义基因表达模式相关的具有可及染色质的非编码区域，我们利用多模态单细胞 RNA 和转座酶可及染色质 (ATAC) 测序数据，对来自 12 名供体的发炎滑膜组织中的 28674 个细胞进行了分析。具体来说，我们使用多元泊松模型从单细胞 RNA 测序主成分预测峰可及性。对于 14 种自身免疫性疾病，我们发现与细胞状态不变（“cs-invariant”）的峰相比，免疫细胞类型中与细胞状态相关（“dynamic”）的染色质可及性峰与遗传率更为相关。这些动态峰标记了与 T 外周辅助、调节性 T、树突状和 STAT1CXCL10 髓样细胞状态相关的调控元件。我们认为，动态调控元件有助于识别富含疾病关键遗传变异的精确细胞状态。
