Genome-wide transcription factor activities are explained by intrinsic conformational dynamics of binding-sites and distal flanking-regions
Genome-wide transcription factor activities are explained by intrinsic conformational dynamics of binding-sites and distal flanking-regions
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DOI：
10.1101/020602
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Munazah Andrabi;A. Hutchins;Diego Miranda-Saavedra;H. Kono;R. Nussinov;K. Mizuguchi;Shandar Ahmad
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文献类型：
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作者：
Munazah Andrabi;A. Hutchins;Diego Miranda-Saavedra;H. Kono;R. Nussinov;K. Mizuguchi;Shandar Ahmad
转录因子（TF）直接或通过其序列依赖性结构识别小的DNA序列基序。虽然序列组成和简并性被证实是TF结合特异性的定义因素，但DNA构象动力学的作用仍然知之甚少。随着来自下一代测序（NGS）数据的越来越多的证据表明仅序列模型的不足，需要用于描述TF结合偏好的替代模型，其中构象动力学呈现有吸引力的选择。在这里，我们报告了一种新的方法（DynaSeq），它准确地预测DNA构象合奏的基因组目标的TF。使用DynaSeq，我们演示了如何动态的结合位点及其远端侧翼区可以用来阐明TF结合模式的两个模型系统：细胞类型特异性结合的STAT 3和染色质结构特异性的3个功能TF类即先锋，定居者和移民。我们发现，在这两个系统中的TF偏好可以准确地解释其结合位点和其远端侧翼DNA区域的构象动力学。构象动力学不仅将结合位点与STAT 3的基因组背景区分开来，还指出了其周围区域的模块化组织。此外，STAT 3-DNA的差异结合模式揭示了细胞特异性的潜在机制。我们的模型确定明确的签名，准确地分类先锋，移民和定居TF目标的远端侧翼区的动态。这表明TF的染色质偏好受到TF结合位点周围DNA的内在构象动力学的显著影响。
Transcription factors (TFs) recognize small DNA sequence motifs directly or through their sequence-dependent structure. While sequence composition and degeneracy are verified to be the defining factors of TF binding specificity, the role of conformational dynamics of the DNA remains poorly understood. With growing evidence from next generation sequencing (NGS) data suggesting the inadequacy of sequence-only models, alternative models for describing the TF binding preferences are required, wherein the conformational dynamics presents an attractive option. Here, we report a novel method (DynaSeq) which accurately predicts DNA-conformational ensembles for genomic targets of TFs. Using DynaSeq we demonstrate how the dynamics of binding sites and their distal flanking regions can be used to elucidate TF-binding patterns for two model systems: cell type-specific binding of STAT3 and chromatin structural specificity of 3 functional TF classes viz. pioneers, settlers and migrants. We find that TF preferences in both these systems can be accurately explained by the conformational dynamics of their binding sites and their distal flanking DNA regions. Conformational dynamics not only distinguishes binding sites from genomic backgrounds in STAT3; it also points to a modular organization of their surrounding regions. Further, the differential binding modes of STAT3-DNA reveal a potential mechanism of cellular specificity. Our model identifies clear signatures to accurately classify pioneer, migrant and settler TF targets from the dynamics of distal flanking regions. This suggests that the chromatin preferences of TFs are significantly influenced by the intrinsic conformational dynamics of the DNA surrounding the TF binding sites.