Single-cell analysis reveals that noncoding RNAs contribute to clonal heterogeneity by modulating transcription factor recruitment.
Single-cell analysis reveals that noncoding RNAs contribute to clonal heterogeneity by modulating transcription factor recruitment.
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DOI：
10.1016/j.molcel.2011.11.029
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发表时间：
2012-02-24
期刊：
影响因子：
16
通讯作者：
Fink, Gerald R.
中科院分区：
文献类型：
--
作者：
Bumgarner, Stacie L.;Neuert, Gregor;Voight, Benjamin F.;Symbor-Nagrabska, Anna;Grisafi, Paula;van Oudenaarden, Alexander;Fink, Gerald R.
长基因间非编码RNA（ncRNA）对真核生物过程发挥调控作用的机制在很大程度上仍然难以捉摸。这些现象的大多数研究依赖于测量细胞群体中平均行为的方法，缺乏观察单个细胞中ncRNA转录对基因表达的影响的分辨率。在这里，我们结合联合收割机定量单分子RNA FISH实验与酵母遗传学和计算建模，以获得机制的见解调节酿酒酵母蛋白编码基因FLO11的两个基因间的ncRNA，ICR 1和PWR 1。在数千个单个细胞中直接检测FLO11 mRNA和这些ncRNA揭示了替代表达状态，并提供了证据表明ICR 1和PWR 1有助于FLO11的多样化转录，通过调节关键转录因子对FLO11启动子的募集，导致克隆细胞群体中的Flo11依赖性表型异质性。
Mechanisms through which long intergenic noncoding RNAs (ncRNAs) exert regulatory effects on eukaryotic biological processes remain largely elusive. Most studies of these phenomena rely on methods that measure average behaviors in cell populations, lacking resolution to observe the effects of ncRNA transcription on gene expression in a single cell. Here, we combine quantitative single-molecule RNA FISH experiments with yeast genetics and computational modeling to gain mechanistic insights into the regulation of the Saccharomyces cerevisiae protein-coding gene FLO11 by two intergenic ncRNAs, ICR1 and PWR1. Direct detection of FLO11 mRNA and these ncRNAs in thousands of individual cells revealed alternative expression states and provides evidence that ICR1 and PWR1 contribute to FLO11’s variegated transcription, resulting in Flo11-dependent phenotypic heterogeneity in clonal cell populations by modulating recruitment of key transcription factors to the FLO11 promoter.
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