Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Open Targets, Wellcome Genome Campus, Cambridge, UK.
Nat Genet. 2019 Oct;51(10):1486-1493. doi: 10.1038/s41588-019-0493-9. Epub 2019 Sep 23.
Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while the presence of cytokines fine-tuned the magnitude of changes. We developed a statistical method that accounts for subtle changes in the chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune-disease-associated variants in early rather than late activation of memory CD4 T cells, with modest differences across cytokines. Furthermore, variants associated with inflammatory bowel disease are enriched in type 1 T helper (T1) cells, whereas variants associated with Alzheimer's disease are enriched in different macrophage cell states. Our results represent an in-depth analysis of immune-disease-associated variants across a comprehensive panel of activation states of T cells and macrophages.
免疫相关疾病变异在 T 细胞和巨噬细胞的活性染色质区域中富集。然而，这些变异是否在特定的细胞状态中发挥作用尚不清楚。在这里，我们在 13 种细胞因子的存在下刺激 T 细胞和巨噬细胞，并对活性和开放染色质区域进行了分析。T 细胞的激活诱导了主要的染色质重塑，而细胞因子的存在则微调了变化的幅度。我们开发了一种统计方法，该方法可以解释染色质景观中的细微变化，从而在细胞状态中识别 SNP 的富集。我们的研究结果表明，免疫相关疾病变异在记忆 CD4 T 细胞的早期而不是晚期激活中起作用，不同细胞因子之间存在差异。此外，与炎症性肠病相关的变异在 1 型 T 辅助细胞（T1）中富集，而与阿尔茨海默病相关的变异在不同的巨噬细胞状态中富集。我们的研究结果代表了对 T 细胞和巨噬细胞的全面激活状态进行免疫相关疾病变异的深入分析。
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