Biophysics Graduate Group, University of California, Berkeley, CA 904720.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Proc Natl Acad Sci U S A. 2023 Mar 7;120(10):e2211203120. doi: 10.1073/pnas.2211203120. Epub 2023 Mar 2.
Gene regulation is central to cellular function. Yet, despite decades of work, we lack quantitative models that can predict how transcriptional control emerges from molecular interactions at the gene locus. Thermodynamic models of transcription, which assume that gene circuits operate at equilibrium, have previously been employed with considerable success in the context of bacterial systems. However, the presence of ATP-dependent processes within the eukaryotic transcriptional cycle suggests that equilibrium models may be insufficient to capture how eukaryotic gene circuits sense and respond to input transcription factor concentrations. Here, we employ simple kinetic models of transcription to investigate how energy dissipation within the transcriptional cycle impacts the rate at which genes transmit information and drive cellular decisions. We find that biologically plausible levels of energy input can lead to significant gains in how rapidly gene loci transmit information but discover that the regulatory mechanisms underlying these gains change depending on the level of interference from noncognate activator binding. When interference is low, information is maximized by harnessing energy to push the sensitivity of the transcriptional response to input transcription factors beyond its equilibrium limits. Conversely, when interference is high, conditions favor genes that harness energy to increase transcriptional specificity by proofreading activator identity. Our analysis further reveals that equilibrium gene regulatory mechanisms break down as transcriptional interference increases, suggesting that energy dissipation may be indispensable in systems where noncognate factor interference is sufficiently large.
基因调控是细胞功能的核心。然而，尽管已经进行了几十年的研究，我们仍然缺乏能够预测转录控制如何从基因位点的分子相互作用中产生的定量模型。转录的热力学模型假设基因回路在平衡状态下运行，以前在细菌系统的背景下已经取得了相当大的成功。然而，真核转录循环中存在 ATP 依赖性过程表明，平衡模型可能不足以捕捉真核基因回路如何感知和响应输入转录因子浓度。在这里，我们采用转录的简单动力学模型来研究转录循环中的能量耗散如何影响基因传递信息和驱动细胞决策的速度。我们发现，生物上合理的能量输入水平可以显著提高基因座传递信息的速度，但发现这些增益背后的调节机制取决于非同源激活剂结合的干扰程度。当干扰较低时，通过利用能量将转录反应对输入转录因子的敏感性推至其平衡极限之外，可以最大化信息。相反，当干扰较高时，有利于利用能量通过校对激活剂身份来提高转录特异性的基因的条件。我们的分析进一步表明，随着转录干扰的增加，平衡基因调控机制崩溃，这表明在非同源因子干扰足够大的系统中，能量耗散可能是必不可少的。
