Distinguishing direct versus indirect transcription factor-DNA interactions
Distinguishing direct versus indirect transcription factor-DNA interactions
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DOI：
10.1101/gr.094144.109
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发表时间：
2009-11-01
期刊：
影响因子：
7
通讯作者：
Bulyk, Martha L.
中科院分区：
文献类型：
--
作者：
Gordan, Raluca;Hartemink, Alexander J.;Bulyk, Martha L.
转录调控主要是由结合 DNA 的转录因子 (TF) 实施的。 ChIP 芯片实验和计算 DNA 基序发现揭示了大量 TF 结合基序。然而，当应用于体内结合的序列（例如通过 ChIP 芯片识别的序列）时，基序发现算法的成功受到限制，因为观察到的 TF-DNA 相互作用不一定是直接的：一些 TF 主要通过蛋白质伴侣与 DNA 间接结合，而另一些则表现出直接和间接结合。在这里，我们提出了第一种区分直接和间接 TF-DNA 相互作用的方法，整合了体内 TF 结合数据、体内核小体占用数据和体外蛋白质结合微阵列实验的基序。当应用于酵母 ChIP 芯片数据时，我们的方法表明，只有 48% 的数据集可以通过分析 TF 的直接结合来解释，而 16% 可以通过间接 DNA 结合来解释。在剩下的 36% 中，我们分析中使用的基序都无法解释 ChIP 芯片数据，要么是因为数据噪音太大，要么是因为基序集不完整。随着更多体外 TF DNA 结合基序的出现，我们的方法可用于构建直接和间接 TF-DNA 相互作用的完整目录。我们的方法不限于酵母或 ChIP 芯片数据，而是可以应用于体内结合数据和体外 DNA 结合基序均可用的任何系统。
Transcriptional regulation is largely enacted by transcription factors (TFs) binding DNA. Large numbers of TF binding motifs have been revealed by ChIP-chip experiments followed by computational DNA motif discovery. However, the success of motif discovery algorithms has been limited when applied to sequences bound in vivo ( such as those identified by ChIP-chip) because the observed TF-DNA interactions are not necessarily direct: Some TFs predominantly associate with DNA indirectly through protein partners, while others exhibit both direct and indirect binding. Here, we present the first method for distinguishing between direct and indirect TF-DNA interactions, integrating in vivo TF binding data, in vivo nucleosome occupancy data, and motifs from in vitro protein binding microarray experiments. When applied to yeast ChIP-chip data, our method reveals that only 48% of the data sets can be readily explained by direct binding of the profiled TF, while 16% can be explained by indirect DNA binding. In the remaining 36%, none of the motifs used in our analysis was able to explain the ChIP-chip data, either because the data were too noisy or because the set of motifs was incomplete. As more in vitro TF DNA binding motifs become available, our method could be used to build a complete catalog of direct and indirect TF-DNA interactions. Our method is not restricted to yeast or to ChIP-chip data, but can be applied in any system for which both in vivo binding data and in vitro DNA binding motifs are available.