Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir 35340, Turkey.
Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir 35340, Turkey.
J Chem Inf Model. 2023 Jun 26;63(12):3839-3853. doi: 10.1021/acs.jcim.2c01520. Epub 2023 Jun 12.
Pioneer transcription factors (PTFs) have the remarkable ability to directly bind to chromatin to stimulate vital cellular processes. In this work, we dissect the universal binding mode of Sox PTF by combining extensive molecular simulations and physiochemistry approaches, along with DNA footprinting techniques. As a result, we show that when Sox consensus DNA is located at the solvent-facing DNA strand, Sox binds to the compact nucleosome without imposing any significant conformational changes. We also reveal that the base-specific Sox:DNA interactions (base reading) and Sox-induced DNA changes (shape reading) are concurrently required for sequence-specific nucleosomal DNA recognition. Among three different nucleosome positions located on the positive DNA arm, a sequence-specific reading mechanism is solely satisfied at the superhelical location 2 (SHL2). While SHL2 acts transparently for solvent-facing Sox binding, among the other two positions, SHL4 permits only shape reading. The final position, SHL0 (dyad), on the other hand, allows no reading mechanism. These findings demonstrate that Sox-based nucleosome recognition is essentially guided by intrinsic nucleosome properties, permitting varying degrees of DNA recognition.
先驱转录因子（PTFs）具有直接结合染色质以刺激重要细胞过程的非凡能力。在这项工作中，我们通过结合广泛的分子模拟和物理化学方法以及 DNA 足迹技术来剖析 Sox PTF 的通用结合模式。结果表明，当 Sox 一致 DNA 位于面向溶剂的 DNA 链上时，Sox 结合到紧凑的核小体而不会引起任何显著的构象变化。我们还揭示了碱基特异性 Sox:DNA 相互作用（碱基读取）和 Sox 诱导的 DNA 变化（形状读取）对于序列特异性核小体 DNA 识别是同时需要的。在位于正 DNA 臂上的三个不同核小体位置中，仅在超螺旋位置 2（SHL2）满足序列特异性读取机制。虽然 SHL2 对面向溶剂的 Sox 结合是透明的，但在其他两个位置中，SHL4 仅允许形状读取。另一方面，最后一个位置 SHL0（二分体）不允许任何读取机制。这些发现表明，基于 Sox 的核小体识别本质上是由内在的核小体特性指导的，允许 DNA 识别具有不同程度。
