Generation of Single-Cell Transcript Variability by Repression.
Generation of Single-Cell Transcript Variability by Repression.
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DOI：
10.1016/j.cub.2017.05.028
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发表时间：
2017-06-19
期刊：
影响因子：
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通讯作者：
Chubb JR
中科院分区：
文献类型：
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作者：
Antolović V;Miermont A;Corrigan AM;Chubb JR
基因表达水平在相似的细胞中差异很大，甚至在克隆细胞群体中也是如此。这些自发表达差异是分化和疾病中细胞命运多样性的基础。产生表达变异的机制尚不清楚。利用单细胞转录组学，我们发现盘基骨柱分化过程中出现的转录变异性主要是由抑制而不是激活驱动的。在广泛的表达水平范围内观察到被抑制基因的变异性增加，表明变异性是主动施加的，而不是伴随抑制的分子数量减少的被动统计效应。这些发现可以用一个简单的转录产物模型来解释，表达由转录触发事件的频率而不是大小控制。我们的研究表明，细胞间差异的产生可能是转录调节基本机制的直接结果。发育过程中的转录变异性主要由抑制产生，抑制衍生的变异性可以由转录频率调节产生，未分化细胞的亚群可以表达发育基因，发育过程中细胞类型之间的差异通常被认为是由特定谱系中激活的基因引起的。在这项研究中，antoloviki等人利用单细胞转录组学表明，细胞之间的差异主要是由被抑制的基因产生的，而不是那些被激活的基因。
Gene expression levels vary greatly within similar cells, even within clonal cell populations. These spontaneous expression differences underlie cell fate diversity in both differentiation and disease. The mechanisms responsible for generating expression variability are poorly understood. Using single-cell transcriptomics, we show that transcript variability emerging during Dictyostelium differentiation is driven predominantly by repression rather than activation. The increased variability of repressed genes was observed over a broad range of expression levels, indicating that variability is actively imposed and not a passive statistical effect of the reduced numbers of molecules accompanying repression. These findings can be explained by a simple model of transcript production, with expression controlled by the frequency, rather than the magnitude, of transcriptional firing events. Our study reveals that the generation of differences between cells can be a direct consequence of the basic mechanisms of transcriptional regulation. Transcript variability during development is generated predominantly by repression Repression-derived variability can arise from frequency modulation of transcription Sub-populations of undifferentiated cells are primed to express developmental genes The differences between cell types that arise during development are usually assumed to result from the genes that are activated in specific lineages. In this study, Antolović et al. show, using single-cell transcriptomics, that differences between cells are generated predominantly by genes that are repressed, not those that are activated.