Transcriptional Infidelity Promotes Heritable Phenotypic Change in a Bistable Gene Network
Transcriptional Infidelity Promotes Heritable Phenotypic Change in a Bistable Gene Network
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DOI：
10.1371/journal.pbio.1000044
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发表时间：
2009-02-01
期刊：
影响因子：
9.8
通讯作者：
Herman, Christophe
中科院分区：
文献类型：
--
作者：
Gordon, Alasdair J. E.;Halliday, Jennifer A.;Herman, Christophe
双稳态表观遗传开关是单细胞和多细胞生物体细胞命运决定的基础。与双稳态开关相关的调节蛋白通常数量较少并且容易受到分子噪音的影响。越来越清楚的是，基因表达中的噪音会影响细胞的命运。尽管已经研究了噪声的起源和后果，但在噪声的起源或建模中并未考虑转录过程中 RNA 错误的随机性和瞬时性，也没有讨论信息传递中的这种瞬时错误产生可遗传表型变化的能力。我们使用经典的双稳态内存模块来监测和捕获瞬时 RNA 错误：大肠杆菌的 lac 操纵子包含一个自催化正反馈回路，产生对分子噪声敏感的可遗传的全或无表观遗传开关。通过单细胞分析，我们发现，当 RNA 转录保真度因容易出错的 RNA 聚合酶或辅助 RNA 保真度因子 GreA 和 GreB（真核生物 TFIIS 的功能类似物）的缺失而降低时，表观遗传从一种表达状态切换到另一种表达状态的频率就会增加。因此，转录不忠实会导致分子噪音，并可能影响相同环境中遗传相同的细胞的可遗传表型变化。 DNA 错误允许探索遗传空间，而 RNA 错误可能允许对表观遗传或表达空间进行采样。因此，在细胞行为改变或异常的遗传起源中也应考虑RNA不忠。
Bistable epigenetic switches are fundamental for cell fate determination in unicellular and multicellular organisms. Regulatory proteins associated with bistable switches are often present in low numbers and subject to molecular noise. It is becoming clear that noise in gene expression can influence cell fate. Although the origins and consequences of noise have been studied, the stochastic and transient nature of RNA errors during transcription has not been considered in the origin or modeling of noise nor has the capacity for such transient errors in information transfer to generate heritable phenotypic change been discussed. We used a classic bistable memory module to monitor and capture transient RNA errors: the lac operon of Escherichia coli comprises an autocatalytic positive feedback loop producing a heritable all-or-none epigenetic switch that is sensitive to molecular noise. Using single-cell analysis, we show that the frequency of epigenetic switching from one expression state to the other is increased when the fidelity of RNA transcription is decreased due to error-prone RNA polymerases or to the absence of auxiliary RNA fidelity factors GreA and GreB (functional analogues of eukaryotic TFIIS). Therefore, transcription infidelity contributes to molecular noise and can effect heritable phenotypic change in genetically identical cells in the same environment. Whereas DNA errors allow genetic space to be explored, RNA errors may allow epigenetic or expression space to be sampled. Thus, RNA infidelity should also be considered in the heritable origin of altered or aberrant cell behaviour.