Raj Arjun, Peskin Charles S, Tranchina Daniel, Vargas Diana Y, Tyagi Sanjay
Courant Institute of Mathematical Sciences, New York University, New York, New York, USA.
PLoS Biol. 2006 Oct;4(10):e309. doi: 10.1371/journal.pbio.0040309.
Individual cells in genetically homogeneous populations have been found to express different numbers of molecules of specific proteins. We investigated the origins of these variations in mammalian cells by counting individual molecules of mRNA produced from a reporter gene that was stably integrated into the cell's genome. We found that there are massive variations in the number of mRNA molecules present in each cell. These variations occur because mRNAs are synthesized in short but intense bursts of transcription beginning when the gene transitions from an inactive to an active state and ending when they transition back to the inactive state. We show that these transitions are intrinsically random and not due to global, extrinsic factors such as the levels of transcriptional activators. Moreover, the gene activation causes burst-like expression of all genes within a wider genomic locus. We further found that bursts are also exhibited in the synthesis of natural genes. The bursts of mRNA expression can be buffered at the protein level by slow protein degradation rates. A stochastic model of gene activation and inactivation was developed to explain the statistical properties of the bursts. The model showed that increasing the level of transcription factors increases the average size of the bursts rather than their frequency. These results demonstrate that gene expression in mammalian cells is subject to large, intrinsically random fluctuations and raise questions about how cells are able to function in the face of such noise.
在基因同质的细胞群体中，已发现单个细胞表达特定蛋白质的分子数量不同。我们通过对稳定整合到细胞基因组中的报告基因产生的单个mRNA分子进行计数，研究了哺乳动物细胞中这些变异的起源。我们发现每个细胞中存在的mRNA分子数量有巨大差异。这些差异的出现是因为mRNA是在短暂但强烈的转录爆发中合成的，始于基因从非活性状态转变为活性状态之时，止于它们转变回非活性状态之时。我们表明，这些转变本质上是随机的，并非由于全局性的外在因素，如转录激活因子的水平。此外，基因激活会导致更广泛基因组位点内所有基因的爆发式表达。我们进一步发现，天然基因的合成中也会出现爆发。mRNA表达的爆发在蛋白质水平上可通过缓慢的蛋白质降解速率得到缓冲。我们开发了一个基因激活和失活的随机模型来解释这些爆发的统计特性。该模型表明，增加转录因子的水平会增加爆发的平均大小，而非其频率。这些结果表明，哺乳动物细胞中的基因表达受到巨大的、内在随机波动的影响，并引发了关于细胞在面对这种噪声时如何发挥功能的问题。
