Quantitative modeling of gene expression using DNA shape features of binding sites.
Quantitative modeling of gene expression using DNA shape features of binding sites.
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DOI：
10.1093/nar/gkw446
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发表时间：
2016-07-27
影响因子：
14.9
通讯作者：
Sinha S
中科院分区：
文献类型：
--
作者：
Peng PC;Sinha S
由调控序列驱动的基因表达水平预测在基因组生物学中至关重要。转录调控的一个主要焦点是序列-表达模型，该模型根据转录因子浓度和DNA结合特异性解释增强子序列，并预测不同细胞环境下基因表达水平的精确水平。这些模型在很大程度上依赖于DNA结合的位置权重矩阵（PWM）模型，而基于DNA形状的替代模型的影响仍未被探索。在这里，我们提出了一个利用结合位点的DNA形状特征的基因表达的统计热力学模型。我们使用严格的方法评估了果蝇胚胎中调节空间基因表达模式的37个增强子的表达读数的拟合，并表明基于DNA形状的模型可能比基于pwm的模型表现得更好。我们还观察到DNA形状捕获与PWM互补的信息，这对表达建模很有用。此外，我们测试了结合形状和基于pwm的特征是否比单独使用任何绑定模型提供更好的预测。我们的工作表明，基于局部DNA形状的日益流行的DNA结合模型可以用于序列到表达的建模。它还为未来的研究提供了一个框架，可以比单独使用PWM模型更好地预测基因表达。
Prediction of gene expression levels driven by regulatory sequences is pivotal in genomic biology. A major focus in transcriptional regulation is sequence-to-expression modeling, which interprets the enhancer sequence based on transcription factor concentrations and DNA binding specificities and predicts precise gene expression levels in varying cellular contexts. Such models largely rely on the position weight matrix (PWM) model for DNA binding, and the effect of alternative models based on DNA shape remains unexplored. Here, we propose a statistical thermodynamics model of gene expression using DNA shape features of binding sites. We used rigorous methods to evaluate the fits of expression readouts of 37 enhancers regulating spatial gene expression patterns in Drosophila embryo, and show that DNA shape-based models perform arguably better than PWM-based models. We also observed DNA shape captures information complimentary to the PWM, in a way that is useful for expression modeling. Furthermore, we tested if combining shape and PWM-based features provides better predictions than using either binding model alone. Our work demonstrates that the increasingly popular DNA-binding models based on local DNA shape can be useful in sequence-to-expression modeling. It also provides a framework for future studies to predict gene expression better than with PWM models alone.