Transcription factor family-specific DNA shape readout revealed by quantitative specificity models.
Transcription factor family-specific DNA shape readout revealed by quantitative specificity models.
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DOI：
10.15252/msb.20167238
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发表时间：
2017-02-06
影响因子：
9.9
通讯作者：
Rohs R
中科院分区：
文献类型：
--
作者：
Yang L;Orenstein Y;Jolma A;Yin Y;Taipale J;Shamir R;Rohs R
转录因子（TFs）通过与碱基的官能团（碱基读出）和双螺旋结构特性的读出（形状读出）接触来实现DNA结合特异性。目前，尚不清楚DNA形状读出是否仅被少数选定的TF家族利用，或者该机制是否被大多数TF家族广泛使用。我们对先前发表的HT - SELEX实验数据进行了重新测序，这是迄今为止最广泛的哺乳动物TF-DNA结合数据。利用这些数据，我们证明了DNA形状读出在不同TF家族中的贡献及其在核心基元侧翼区域的重要性。结合特征选择技术的统计机器学习模型有助于揭示TF结合位点的核苷酸位置依赖性DNA形状读出和TF家族特异性位置依赖性。基于这些结果，我们提出了新的DNA形状标识来可视化tf的DNA形状偏好。总的来说，这项工作提出了一种不依赖于实验解决的全原子结构而获得TF-DNA结合机制的方法。
Transcription factors (TFs) achieve DNA‐binding specificity through contacts with functional groups of bases (base readout) and readout of structural properties of the double helix (shape readout). Currently, it remains unclear whether DNA shape readout is utilized by only a few selected TF families, or whether this mechanism is used extensively by most TF families. We resequenced data from previously published HT‐SELEX experiments, the most extensive mammalian TF–DNA binding data available to date. Using these data, we demonstrated the contributions of DNA shape readout across diverse TF families and its importance in core motif‐flanking regions. Statistical machine‐learning models combined with feature‐selection techniques helped to reveal the nucleotide position‐dependent DNA shape readout in TF‐binding sites and the TF family‐specific position dependence. Based on these results, we proposed novel DNA shape logos to visualize the DNA shape preferences of TFs. Overall, this work suggests a way of obtaining mechanistic insights into TF–DNA binding without relying on experimentally solved all‐atom structures.