Nature2014-06-23 4:49 PM

跟踪基因表达的变化 Single-cell RNA-seq reveals dynamic paracrine control of cellular variation

论文摘要 

“高吞吐量单细胞转录组”为了解细胞之间的基因表达差异提供了一个无偏颇的方法。在这篇论文中,Aviv Regev及同事发表了从来自小鼠骨髓、受到各种不同扰动(包括在隔离的、封闭的微流体室中对单个细胞进行刺激以及通过遗传和化学方式来改变旁泌性信号传导)的原始树突细胞获得的单细胞RNA-seq库。这些结果显示了树突细胞的抗病毒和炎症反应模块是怎样被细胞间旁泌性正负反馈环(二者既促进、又限制差异的发生)控制的。

Abstract 

High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis and function of gene expression variation between seemingly identical cells. Here we sequence single-cell RNA-seq libraries prepared from over 1,700 primary mouse bone-marrow-derived dendritic cells spanning several experimental conditions. We find substantial variation between identically stimulated dendritic cells, in both the fraction of cells detectably expressing a given messenger RNA and the transcript’s level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a ‘core’ module of antiviral genes is expressed very early by a few ‘precocious’ cells in response to uniform stimulation with a pathogenic component, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analysing dendritic cells from knockout mice, and modulating secretion and extracellular signalling, we show that this response is coordinated by interferon-mediated paracrine signalling from these precocious cells. Notably, preventing cell-to-cell communication also substantially reduces variability between cells in the expression of an early-induced ‘peaked’ inflammatory module, suggesting that paracrine signalling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations can use to establish complex dynamic responses.

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