Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
Program in Bioinformatics and Systems Biology, University of California, San Diego, San Diego, CA, USA.
Mol Syst Biol. 2020 Feb;16(2):e9146. doi: 10.15252/msb.20199146.
Gene expression variability in mammalian systems plays an important role in physiological and pathophysiological conditions. This variability can come from differential regulation related to cell state (extrinsic) and allele-specific transcriptional bursting (intrinsic). Yet, the relative contribution of these two distinct sources is unknown. Here, we exploit the qualitative difference in the patterns of covariance between these two sources to quantify their relative contributions to expression variance in mammalian cells. Using multiplexed error robust RNA fluorescent in situ hybridization (MERFISH), we measured the multivariate gene expression distribution of 150 genes related to Ca signaling coupled with the dynamic Ca response of live cells to ATP. We show that after controlling for cellular phenotypic states such as size, cell cycle stage, and Ca response to ATP, the remaining variability is effectively at the Poisson limit for most genes. These findings demonstrate that the majority of expression variability results from cell state differences and that the contribution of transcriptional bursting is relatively minimal.
哺乳动物系统中的基因表达变异性在生理和病理生理条件中起着重要作用。这种变异性可能来自于与细胞状态相关的差异调节（外在的）和等位基因特异性转录爆发（内在的）。然而，这两个不同来源的相对贡献尚不清楚。在这里，我们利用这两种来源之间协方差模式的定性差异来量化它们对哺乳动物细胞表达方差的相对贡献。我们使用多重误差稳健 RNA 荧光原位杂交（MERFISH），测量了 150 个与 Ca 信号相关的基因的多变量基因表达分布，同时结合了活细胞对 ATP 的动态 Ca 反应。我们表明，在控制了细胞表型状态（如大小、细胞周期阶段和对 ATP 的 Ca 反应）之后，对于大多数基因，剩余的变异性实际上接近泊松极限。这些发现表明，大多数表达变异性来自于细胞状态差异，而转录爆发的贡献相对较小。
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