A widespread role of the motif environment in transcription factor binding across diverse protein families.
A widespread role of the motif environment in transcription factor binding across diverse protein families.
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DOI：
10.1101/gr.184671.114
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发表时间：
2015-09
期刊：
影响因子：
7
通讯作者：
Mandel-Gutfreund Y
中科院分区：
文献类型：
--
作者：
Dror I;Golan T;Levy C;Rohs R;Mandel-Gutfreund Y
转录调控需要转录因子（TF）与通常位于基因调控区的短序列特异性DNA基序结合。有趣的是，基于从基因组测定中积累的大量数据，已经表明，含有给定TF的共有基序的所有潜在结合位点中只有一小部分实际上结合蛋白质。最近的体外结合试验，排除了细胞环境的影响，也证明了选择性TF结合。一个有趣的猜想是，同源结合位点的周围环境具有独特的特征，将它们与含有不被TF结合的类似基序的其他序列区分开来。为了验证这一假设，我们对分别从体外HT-SELEX结合试验和体内ChIP-seq数据中提取的239和56个TF的核心结合位点周围的序列和DNA形状特征进行了全面分析。将TF结合位点周围区域的核苷酸含量与含有相同共识基序的对应未结合区域进行比较，发现了远远超出核心结合位点的显著差异。具体而言，结合基序的环境表现出独特的序列组成，DNA形状特征，以及与核心结合基序的整体高度相似性。值得注意的是，属于相同TF家族的TF的结合位点周围的区域表现出相似的特征，在体外和体内数据集之间具有高度一致性。我们建议，这些独特的功能有助于指导TF的同源结合位点。
Transcriptional regulation requires the binding of transcription factors (TFs) to short sequence-specific DNA motifs, usually located at the gene regulatory regions. Interestingly, based on a vast amount of data accumulated from genomic assays, it has been shown that only a small fraction of all potential binding sites containing the consensus motif of a given TF actually bind the protein. Recent in vitro binding assays, which exclude the effects of the cellular environment, also demonstrate selective TF binding. An intriguing conjecture is that the surroundings of cognate binding sites have unique characteristics that distinguish them from other sequences containing a similar motif that are not bound by the TF. To test this hypothesis, we conducted a comprehensive analysis of the sequence and DNA shape features surrounding the core-binding sites of 239 and 56 TFs extracted from in vitro HT-SELEX binding assays and in vivo ChIP-seq data, respectively. Comparing the nucleotide content of the regions around the TF-bound sites to the counterpart unbound regions containing the same consensus motifs revealed significant differences that extend far beyond the core-binding site. Specifically, the environment of the bound motifs demonstrated unique sequence compositions, DNA shape features, and overall high similarity to the core-binding motif. Notably, the regions around the binding sites of TFs that belong to the same TF families exhibited similar features, with high agreement between the in vitro and in vivo data sets. We propose that these unique features assist in guiding TFs to their cognate binding sites.