Feedback from nuclear RNA on transcription promotes robust RNA concentration homeostasis in human cells
Feedback from nuclear RNA on transcription promotes robust RNA concentration homeostasis in human cells
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DOI：
10.1016/j.cels.2022.04.005
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发表时间：
2022-06-15
期刊：
影响因子：
9.3
通讯作者：
Pelkmans, Lucas
中科院分区：
文献类型：
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作者：
Berry, Scott;Muller, Micha;Pelkmans, Lucas
RNA浓度稳态涉及协调RNA丰度和合成速率与细胞大小。在这里，我们通过将全基因组扰动与定量单细胞测量相结合来研究人类细胞中的这一点。尽管干扰RNA合成相对容易，但我们发现RNA浓度通常保持高度恒定。预期增加核mRNA水平的扰动，包括靶向核mRNA降解或输出的扰动，导致RNA合成下调。这与转录相关蛋白质和蛋白质状态的丰度降低有关，这些蛋白质状态通常与单细胞中的RNA产生协调，包括RNA聚合酶II（RNA Pol II）本身。急性扰动，核mRNA水平的升高和数学建模表明，哺乳动物细胞通过基于mRNA的核转录活性负反馈实现稳健的mRNA浓度稳态。这最终起到协调RNA Pol II丰度与核mRNA降解和输出速率的作用，并且可以支持mRNA丰度与细胞大小的缩放。
RNA concentration homeostasis involves coordinating RNA abundance and synthesis rates with cell size. Here, we study this in human cells by combining genome-wide perturbations with quantitative single-cell measurements. Despite relative ease in perturbing RNA synthesis, we find that RNA concentrations generally remain highly constant. Perturbations that would be expected to increase nuclear mRNA levels, including those targeting nuclear mRNA degradation or export, result in downregulation of RNA synthesis. This is associated with reduced abundance of transcription-associated proteins and protein states that are normally coordinated with RNA production in single cells, including RNA polymerase II (RNA Pol II) itself. Acute perturbations, elevation of nuclear mRNA levels, and mathematical modeling indicate that mammalian cells achieve robust mRNA concentration homeostasis by the mRNA-based negative feedback on transcriptional activity in the nucleus. This ultimately acts to coordinate RNA Pol II abundance with nuclear mRNA degradation and export rates and may underpin the scaling of mRNA abundance with cell size.