贝叶斯统计和系留粒子运动揭示的多个Lac介导环
Multiple Lac-mediated loops revealed by Bayesian statistics and tethered particle motion
摘要：
细菌转录因子LacI通过同时结合到DNA上的两个独立位置来使DNA成环。尽管是一个最好的研究模型系统的转录调控，环结构的数量和构象的访问LacI仍然不清楚，虽然多个共存的循环的重要性已被牵连在LacI和其他细胞调节基因表达之间的相互作用。为了探讨这个问题，我们已经开发了一种新的分析方法拴系粒子运动，一个通用的和常用的体外单分子技术。我们的方法，vbTPM，进行变分贝叶斯推断隐马尔可夫模型。它学习不同状态的数量（即，DNA-蛋白质构象）直接从系留粒子运动数据，具有比现有方法更好的分辨率，同时容易校正常见的实验伪影。研究短（约100 bp）的LacI介导的环，我们提供了三个不同的环结构的证据，比以前报道的单分子研究。此外，我们的研究结果证实，LacI构象和DNA结合拓扑结构的变化都有助于在体外形成的LacI介导的环的剧目，并提供定性的循环和转录调控模型的新输入。我们预计vbTPM将广泛用于探测复杂的蛋白质-核酸相互作用。
英文摘要：
The bacterial transcription factor LacI loops DNA by binding to two separate locations on the DNA simultaneously. Despite being one of the best-studied model systems for transcriptional regulation, the number and conformations of loop structures accessible to LacI remain unclear, though the importance of multiple co-existing loops has been implicated in interactions between LacI and other cellular regulators of gene expression. To probe this issue, we have developed a new analysis method for tethered particle motion, a versatile and commonly-used in vitro single-molecule technique. Our method, vbTPM, performs variational Bayesian inference in hidden Markov models. It learns the number of distinct states (i.e., DNA-protein conformations) directly from tethered particle motion data with better resolution than existing methods, while easily correcting for common experimental artifacts. Studying short (roughly 100 bp) LacI-mediated loops, we provide evidence for three distinct loop structures, more than previously reported in single-molecule studies. Moreover, our results confirm that changes in LacI conformation and DNA binding topology both contribute to the repertoire of LacI-mediated loops formed in vitro, and provide qualitatively new input for models of looping and transcriptional regulation. We expect vbTPM to be broadly useful for probing complex protein-nucleic acid interactions.
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