Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure.
Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure.
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DOI：
10.1038/s41467-022-30893-5
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发表时间：
2022-06-07
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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宿主的基因表达和对病原体暴露的基因调节反应可以受到宿主的遗传背景、病原体的类型和暴露时间的组合的影响。在这里，我们提供了一个详细的解剖，这使用单细胞RNA测序的1.3M外周血单核细胞从120个人，纵向暴露于三种不同的病原体。这些分析表明，关于影响遗传学如何影响基因表达的背景，细胞类型特异性是比病原体特异性更突出的因素（即，eQTL）和共表达（即，共表达QTL）。在单核细胞中，对病原体刺激的最强反应者，71.4%的遗传变异对基因表达的影响受到病原体暴露的影响（即，响应QTL）也影响基因间的共表达。这表明基因表达水平及其调控的广泛的、背景特异性的变化是由遗传学驱动的。CLEC12A基因的途径分析，阐明了细胞类型，时间和遗传背景依赖性的共表达相互作用，显示富集的干扰素（IFN）途径，特别是在3小时后暴露在单核细胞。通过计算机模拟分析证实了系统性红斑狼疮中IFN活性和CLEC12A共表达模式之间存在类似的遗传背景依赖性关联，这意味着CLEC12A可能是IFN调节的基因。总之，这项研究强调了背景对于更好地理解健康和疾病中基因调控机制的重要性。免疫细胞中的差异基因表达和差异基因调控不仅解释了免疫应答的个体差异。作者通过对来自大量遗传多样性个体的外周血单核细胞的单细胞RNA测序表明，这些细胞中的基因表达和调控变化取决于细胞类型、遗传学、病原体类型和暴露后时间的背景和相互作用。
The host’s gene expression and gene regulatory response to pathogen exposure can be influenced by a combination of the host’s genetic background, the type of and exposure time to pathogens. Here we provide a detailed dissection of this using single-cell RNA-sequencing of 1.3M peripheral blood mononuclear cells from 120 individuals, longitudinally exposed to three different pathogens. These analyses indicate that cell-type-specificity is a more prominent factor than pathogen-specificity regarding contexts that affect how genetics influences gene expression (i.e., eQTL) and co-expression (i.e., co-expression QTL). In monocytes, the strongest responder to pathogen stimulations, 71.4% of the genetic variants whose effect on gene expression is influenced by pathogen exposure (i.e., response QTL) also affect the co-expression between genes. This indicates widespread, context-specific changes in gene expression level and its regulation that are driven by genetics. Pathway analysis on the CLEC12A gene that exemplifies cell-type-, exposure-time- and genetic-background-dependent co-expression interactions, shows enrichment of the interferon (IFN) pathway specifically at 3-h post-exposure in monocytes. Similar genetic background-dependent association between IFN activity and CLEC12A co-expression patterns is confirmed in systemic lupus erythematosus by in silico analysis, which implies that CLEC12A might be an IFN-regulated gene. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease. Not just differential gene expression but also differential gene regulation in immune cells account for individual differences in the immune response. Authors show here by single-cell RNA-sequencing of peripheral blood mononuclear cells from a large cohort of genetically diverse individuals that gene expression and regulatory changes in these cells depend on the context of and interactions between cell types, genetics, type of pathogen and time after exposure.
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影响因子：
64.8
作者：
Hagai T;Chen X;Miragaia RJ;Rostom R;Gomes T;Kunowska N;Henriksson J;Park JE;Proserpio V;Donati G;Bossini-Castillo L;Vieira Braga FA;Naamati G;Fletcher J;Stephenson E;Vegh P;Trynka G;Kondova I;Dennis M;Haniffa M;Nourmohammad A;Lässig M;Teichmann SA
通讯作者：
Teichmann SA
DOI：
10.1073/pnas.1115761109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Barreiro, Luis B.;Tailleux, Ludovic;Gilad, Yoav
通讯作者：
Gilad, Yoav
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG
影响因子：
30.8
作者：
Bentham J;Morris DL;Graham DSC;Pinder CL;Tombleson P;Behrens TW;Martín J;Fairfax BP;Knight JC;Chen L;Replogle J;Syvänen AC;Rönnblom L;Graham RR;Wither JE;Rioux JD;Alarcón-Riquelme ME;Vyse TJ
通讯作者：
Vyse TJ
影响因子：
8.8
作者：
Begun J;Lassen KG;Jijon HB;Baxt LA;Goel G;Heath RJ;Ng A;Tam JM;Kuo SY;Villablanca EJ;Fagbami L;Oosting M;Kumar V;Schenone M;Carr SA;Joosten LA;Vyas JM;Daly MJ;Netea MG;Brown GD;Wijmenga C;Xavier RJ
通讯作者：
Xavier RJ