Gene-Specific Linear Trends Constrain Transcriptional Variability of the Toll-like Receptor Signaling.
Gene-Specific Linear Trends Constrain Transcriptional Variability of the Toll-like Receptor Signaling.
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DOI：
10.1016/j.cels.2020.08.007
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发表时间：
2020-09-23
期刊：
影响因子：
9.3
通讯作者：
Paszek P
中科院分区：
文献类型：
--
作者：
Bagnall J;Rowe W;Alachkar N;Roberts J;England H;Clark C;Platt M;Jackson DA;Muldoon M;Paszek P
单细胞基因表达是固有的可变性，但这种可变性是如何控制的刺激仍不清楚。在这里，我们使用单细胞RNA-seq和单分子mRNA计数（smFISH）来研究免疫toll样受体系统中的诱导型基因表达。我们发现，肿瘤坏死因子α的mRNA计数符合标准的随机开关模型，而白细胞介素-1 β的转录涉及额外的调节步骤，导致异质性增加。尽管调控模式不同，但对一系列基因的单细胞数据的系统分析表明，转录本计数的变异性在一系列条件下受到平均响应的线性约束。smFISH计数和染色质状态的实验扰动的数学建模表明，线性约束出现通过调制的转录爆发沿着与基因特异性的关系。总体而言，我们的分析表明，可诱导的单细胞mRNA反应的变异性受到转录爆发的限制。单细胞TNF-α和IL-1β mRNA反应受差异控制TLR诱导反应的变异性与平均mRNA计数呈线性关系通过转录爆发的调节出现基因特异性限制染色质状态调节IL-1β的转录爆发本研究表明，Toll样受体信号传导的转录变异性通过转录爆发的基因特异性调节受到平均mRNA反应的限制。
Single-cell gene expression is inherently variable, but how this variability is controlled in response to stimulation remains unclear. Here, we use single-cell RNA-seq and single-molecule mRNA counting (smFISH) to study inducible gene expression in the immune toll-like receptor system. We show that mRNA counts of tumor necrosis factor α conform to a standard stochastic switch model, while transcription of interleukin-1β involves an additional regulatory step resulting in increased heterogeneity. Despite different modes of regulation, systematic analysis of single-cell data for a range of genes demonstrates that the variability in transcript count is linearly constrained by the mean response over a range of conditions. Mathematical modeling of smFISH counts and experimental perturbation of chromatin state demonstrates that linear constraints emerge through modulation of transcriptional bursting along with gene-specific relationships. Overall, our analyses demonstrate that the variability of the inducible single-cell mRNA response is constrained by transcriptional bursting. Single-cell TNF-α and IL-1β mRNA responses are differentially controlled Variability of TLR-induced responses scale linearly with mean mRNA counts Gene-specific constraints emerge via modulation of transcriptional bursting Chromatin state regulates transcriptional bursting of IL-1β This study demonstrates that transcriptional variability of the toll-like receptor signaling is constrained by mean mRNA responses through gene-specific modulation of transcriptional bursting.
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影响因子：
16.6
作者：
Daniels MJ;Rivers-Auty J;Schilling T;Spencer NG;Watremez W;Fasolino V;Booth SJ;White CS;Baldwin AG;Freeman S;Wong R;Latta C;Yu S;Jackson J;Fischer N;Koziel V;Pillot T;Bagnall J;Allan SM;Paszek P;Galea J;Harte MK;Eder C;Lawrence CB;Brough D
通讯作者：
Brough D
影响因子：
12.3
作者：
Gómez-Schiavon M;Chen LF;West AE;Buchler NE
通讯作者：
Buchler NE
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
影响因子：
56.9
作者：
Femino, A;Fay, FS;Singer, RH
通讯作者：
Singer, RH
深度测序揭示了单细胞转录组变化的细胞类型特异性模式。
影响因子：
12.3
作者：
Dueck H;Khaladkar M;Kim TK;Spaethling JM;Francis C;Suresh S;Fisher SA;Seale P;Beck SG;Bartfai T;Kuhn B;Eberwine J;Kim J
通讯作者：
Kim J