Origins of extrinsic variability in eukaryotic gene expression
Origins of extrinsic variability in eukaryotic gene expression
复制标题
DOI：
10.1038/nature04281
复制
发表时间：
2006-02-16
期刊：
影响因子：
64.8
通讯作者：
Hasty, J
中科院分区：
文献类型：
--
作者：
Volfson, D;Marciniak, J;Hasty, J
细胞克隆群内的可变基因表达与许多重要过程有关，包括突变和进化(1,2)、细胞命运的决定(3,4) 和遗传疾病的发展(5,6)。最近的研究表明，表达变异的一个重要组成部分是由同时影响多个基因的外在因素引起的(7-10)，但这种外在变异的生物学起源却很少受到关注。在这里，我们将计算模型（11-18）与酿酒酵母中多个启动子基因插入生成的荧光数据相结合，以确定外在变异的两个主要来源。基因表达与群体动态耦合产生的一个不可避免的来源导致普遍存在的表达变异性下限。第二个来源被建模为源自常见的上游转录因子，举例说明了调控网络如何将上游调控因子表达中的噪声转化为目标基因输出处的外在噪声(9)。我们的结果强调了基因调控网络与群体异质性的相互作用对于理解细胞多样性的起源的重要性。
Variable gene expression within a clonal population of cells has been implicated in a number of important processes including mutation and evolution(1,2), determination of cell fates(3,4) and the development of genetic disease(5,6). Recent studies have demonstrated that a significant component of expression variability arises from extrinsic factors thought to influence multiple genes simultaneously(7-10), yet the biological origins of this extrinsic variability have received little attention. Here we combine computational modelling(11-18) with fluorescence data generated from multiple promoter - gene inserts in Saccharomyces cerevisiae to identify two major sources of extrinsic variability. One unavoidable source arising from the coupling of gene expression with population dynamics leads to a ubiquitous lower limit for expression variability. A second source, which is modelled as originating from a common upstream transcription factor, exemplifies how regulatory networks can convert noise in upstream regulator expression into extrinsic noise at the output of a target gene(9). Our results highlight the importance of the interplay of gene regulatory networks with population heterogeneity for understanding the origins of cellular diversity.