Röschinger Tom, Lee Heun Jin, Pan Rosalind Wenshan, Solini Grace, Faizi Kian, Quan Baiyi, Chou Tsui-Fen, Mani Madhav, Quake Stephen, Phillips Rob
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Department of Applied Physics, California Institute of Technology, Pasadena, CA 91125, USA.
bioRxiv. 2025 May 15:2025.05.13.653802. doi: 10.1101/2025.05.13.653802.
All cells respond to changes in both their internal milieu and the environment around them through the regulation of their genes. Despite decades of effort, there remain huge gaps in our knowledge of both the function of many genes (the so-called y-ome) and how they adapt to changing environments via regulation. Here we describe a joint experimental and theoretical dissection of the regulation of a broad array of over 100 biologically interesting genes in across 39 diverse environments, permitting us to discover the binding sites and transcription factors that mediate regulatory control. Using a combination of mutagenesis, massively parallel reporter assays, mass spectrometry and tools from information theory and statistical physics, we go from complete ignorance of a promoter's environment-dependent regulatory architecture to predictive models of its behavior. As a proof of principle of the biological insights to be gained from such a study, we chose a combination of genes from the y-ome, toxin-antitoxin pairs, and genes hypothesized to be part of regulatory modules; in all cases, we discovered a host of new insights into their underlying regulatory landscape and resulting biological function.
所有细胞都通过基因调控来响应其内部环境和周围环境的变化。尽管经过数十年的努力，但我们在许多基因的功能（即所谓的y-ome）以及它们如何通过调控适应不断变化的环境方面，仍然存在巨大的知识差距。在这里，我们描述了一项联合实验和理论研究，对跨越39种不同环境的100多个生物学上有趣的基因的调控进行剖析，使我们能够发现介导调控控制的结合位点和转录因子。通过结合诱变、大规模平行报告基因检测、质谱分析以及信息论和统计物理学的工具，我们从对启动子的环境依赖性调控结构完全无知，到建立其行为的预测模型。作为从这样一项研究中获得生物学见解的原理证明，我们选择了来自y-ome的一组基因、毒素-抗毒素对以及假设为调控模块一部分的基因；在所有情况下，我们都对它们潜在的调控格局和由此产生的生物学功能有了许多新的见解。
