Department of Experimental Oncology, European Institute of Oncology, IFOM-IEO Campus, 20139 Milan, Italy.
Mol Cell. 2010 Feb 12;37(3):418-28. doi: 10.1016/j.molcel.2010.01.016.
A paradigm in transcriptional regulation is that graded increases in transcription factor (TF) concentration are translated into on/off transcriptional responses by cooperative TF binding to adjacent sites. Digital transcriptional responses underlie the definition of anatomical boundaries during development. Here we show that NF-kappaB, a TF controlling inflammation and immunity, is conversely an analog transcriptional regulator that uses clustered binding sites noncooperatively. We observed that increasing concentrations of NF-kappaB are translated into gradual increments in gene transcription. We provide a thermodynamic interpretation of the experimental observations by combining quantitative measurements and a minimal physical model of an NF-kappaB-dependent promoter. We demonstrate that NF-kappaB binds independently to adjacent sites to promote additive RNA Pol II recruitment and graded transcriptional outputs. These findings reveal an alternative mode of operation of clustered TF binding sites, which might function in biological conditions where the transcriptional output is proportional to the strength of an environmental input.
转录调控的一个范例是，转录因子 (TF) 浓度的分级增加通过 TF 与相邻位点的协同结合转化为转录的“开”或“关”反应。数字转录反应是发育过程中定义解剖边界的基础。在这里，我们表明，控制炎症和免疫的 TF NF-κB 相反是一种模拟转录调节剂，它通过非协同方式使用聚集的结合位点。我们观察到 NF-κB 浓度的增加转化为基因转录的逐渐增加。我们通过结合定量测量和 NF-κB 依赖启动子的最小物理模型，对实验观察结果进行了热力学解释。我们证明 NF-κB 独立地结合到相邻的位点以促进 RNA Pol II 的募集和分级转录输出。这些发现揭示了聚集 TF 结合位点的另一种作用模式，它可能在转录输出与环境输入强度成正比的生物条件下发挥作用。
