Cell-cycle dependence of transcription dominates noise in gene expression.
Cell-cycle dependence of transcription dominates noise in gene expression.
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DOI：
10.1371/journal.pcbi.1003161
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发表时间：
2013
影响因子：
4.3
通讯作者：
Maheshri N
中科院分区：
文献类型：
--
作者：
Zopf CJ;Quinn K;Zeidman J;Maheshri N
从单细胞的静态和动态测量中发现的mRNA和蛋白质水平的大的可变性在很大程度上归因于随机的转录周期，通常以爆发的形式发生。细胞周期在影响转录和翻译输出方面具有明显的全局作用，但这如何影响来自嘈杂启动子的转录统计是未知的，并且通常被当前的随机模型所忽略。在这里，我们展示了在S.酿酒酵母是由其对细胞周期的依赖性主导的。在高表达水平下的荧光蛋白的实时测量表明tetO启动子在S/G2/M中使转录速率增加约2倍，类似于组成型基因。在低表达水平下，其中tetO启动子被认为产生不频繁的转录爆发，我们观察到限制于S/G2/M的表达的随机脉冲，其在相同细胞中存在的同源启动子之间相关。对细胞周期沿着不同点的静态单细胞mRNA测量结果的分析证实了这些发现。我们的研究结果表明，酵母中高度可变的mRNA分布不仅仅是活性和非活性基因表达时期之间随机切换的结果，而是主要由G1和S/G2/M之间转录活性的差异驱动。在相同的环境中生长的基因相同的单细胞之间，由特定基因产生的mRNA和蛋白质分子的数量有着惊人的变化。特别是对于mRNA，从这些“噪声”基因中看到的大的变化与转录爆发的想法一致，其中转录发生在随机的、间歇性的高活性时期。转录爆发有相当多的实验支持，它是基因表达随机模型的主要特征，可以解释变异。尽管如此，人们早就认识到，变异，特别是蛋白质水平的变异，可能是由于遗传相同的细胞之间的整体差异而发生的。我们发现，在芽殖酵母中，mRNA的变化在很大程度上是由细胞周期不同阶段之间的噪声基因的转录活性差异驱动的。这些差异并不是因为特定的细胞周期调控，在某些情况下，转录似乎仅限于某些阶段，导致mRNA产生的脉冲。这些结果提出了新的问题，转录爆发的起源和基因表达的统计数据是如何在一个全球性的方式调节细胞周期。
The large variability in mRNA and protein levels found from both static and dynamic measurements in single cells has been largely attributed to random periods of transcription, often occurring in bursts. The cell cycle has a pronounced global role in affecting transcriptional and translational output, but how this influences transcriptional statistics from noisy promoters is unknown and generally ignored by current stochastic models. Here we show that variable transcription from the synthetic tetO promoter in S. cerevisiae is dominated by its dependence on the cell cycle. Real-time measurements of fluorescent protein at high expression levels indicate tetO promoters increase transcription rate ∼2-fold in S/G2/M similar to constitutive genes. At low expression levels, where tetO promoters are thought to generate infrequent bursts of transcription, we observe random pulses of expression restricted to S/G2/M, which are correlated between homologous promoters present in the same cell. The analysis of static, single-cell mRNA measurements at different points along the cell cycle corroborates these findings. Our results demonstrate that highly variable mRNA distributions in yeast are not solely the result of randomly switching between periods of active and inactive gene expression, but instead largely driven by differences in transcriptional activity between G1 and S/G2/M. There is an astonishing amount of variation in the number of mRNA and protein molecules generated from particular genes between genetically identical single cells grown in the same environment. Particularly for mRNA, the large variation seen from these “noisy” genes is consistent with the idea of transcriptional bursting where transcription occurs in random, intermittent periods of high activity. There is considerable experimental support for transcriptional bursting, and it is a primary feature of stochastic models of gene expression that account for variation. Still, it has long been recognized that variation, especially in protein levels, can occur because of global differences between genetically identical cells. We show that in budding yeast, mRNA variation is driven to a large extent by differences in the transcriptional activity of a noisy gene between different phases of the cell cycle. These differences are not because of specific cell-cycle regulation, and in some cases transcription appears restricted to certain phases, leading to pulses of mRNA production. These results raise new questions about the origins of transcriptional bursting and how the statistics of gene expression are regulated in a global way by the cell cycle.
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DOI：
10.1126/science.1202142
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Larson DR;Zenklusen D;Wu B;Chao JA;Singer RH
通讯作者：
Singer RH
影响因子：
48
作者：
Gordon, Andrew;Colman-Lerner, Alejandro;Brent, Roger
通讯作者：
Brent, Roger
影响因子：
3.2
作者：
BOEHLKE, KW;FRIESEN, JD
通讯作者：
FRIESEN, JD
影响因子：
64.8
作者：
Dynlacht, BD
通讯作者：
Dynlacht, BD
DOI：
10.1126/science.1161427
发表时间：
2008-10-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choi PJ;Cai L;Frieda K;Xie XS
通讯作者：
Xie XS