Genome-wide Analyses of Chromatin State in Human Mast Cells Reveal Molecular Drivers and Mediators of Allergic and Inflammatory Diseases
Genome-wide Analyses of Chromatin State in Human Mast Cells Reveal Molecular Drivers and Mediators of Allergic and Inflammatory Diseases
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DOI：
10.1016/j.immuni.2019.09.021
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发表时间：
2019-11-19
期刊：
影响因子：
32.4
通讯作者：
Tergaonkar, Vinay
中科院分区：
文献类型：
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作者：
Cildir, Gokhan;Toubia, John;Tergaonkar, Vinay
肥大细胞（MC）是一种多功能的免疫细胞，能够快速响应各种细胞外信号。在这里，我们绘制了人类MC在不同刺激下的基因组和转录组变化。我们的分析揭示了广泛的H3K4me3结构域和与激活相关的增强子。值得注意的是，免疫球蛋白E（IgE）介导的高亲和力IgE受体（Fc ε RI）交联后细胞内钙浓度的升高导致染色质景观的全基因组重组，并与特定的染色质签名相关，我们称之为Ca2+依赖性开放染色质（COC）结构域。差异表达基因的检查揭示了MC功能的潜在效应子，我们提供了纤维蛋白原样蛋白2（FGL 2）作为MC介质与慢性自发性荨麻疹的潜在相关性的证据。疾病相关的单核苷酸多态性映射到人类MC的顺式调节区表明，MC功能可能会影响广泛的病理。这里提供的数据集构成了进一步研究MC功能的资源。
Mast cells (MCs) are versatile immune cells capable of rapidly responding to a diverse range of extracellular cues. Here, we mapped the genomic and transcriptomic changes in human MCs upon diverse stimuli. Our analyses revealed broad H3K4me3 domains and enhancers associated with activation. Notably, the rise of intracellular calcium concentration upon immunoglobulin E (IgE)-mediated crosslinking of the high-affinity IgE receptor (Fc epsilon RI) resulted in genome-wide reorganization of the chromatin landscape and was associated with a specific chromatin signature, which we term Ca2+dependent open chromatin (COC) domains. Examination of differentially expressed genes revealed potential effectors of MC function, and we provide evidence for fibrinogen-like protein 2 (FGL2) as an MC mediator with potential relevance in chronic spontaneous urticaria. Disease-associated singlenucleotide polymorphisms mapped onto cis-regulatory regions of human MCs suggest that MC function may impact a broad range of pathologies. The datasets presented here constitute a resource for the further study of MC function.