Widespread evidence of cooperative DNA binding by transcription factors in Drosophila development.
Widespread evidence of cooperative DNA binding by transcription factors in Drosophila development.
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DOI：
10.1093/nar/gkt598
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发表时间：
2013-09
影响因子：
14.9
通讯作者：
Sinha S
中科院分区：
文献类型：
--
作者：
Kazemian M;Pham H;Wolfe SA;Brodsky MH;Sinha S
真核基因转录的调节本质上通常是组合的，多个转录因子（TF）通常通过直接或间接的相互作用来调节共同的靶基因。已经确定了许多通过直接相互作用的转录因子进行合作结合的实例，但目前尚不清楚这种机制在动物发育过程中有多普遍。协同 TF 结合应在基因组序列中表现为 TF 结合位点的偏向排列。在这里，我们探讨了果蝇胚胎发生过程中与基因调控相关的这种排列的程度和多样性。我们使用 322 个 TF 的 DNA 结合特异性以及染色质可及性信息来识别 TF 结合位点对的丰富间距和方向模式。我们为此任务开发了一种新的统计方法，专门设计用于准确评估位点间间距偏差，同时考虑发育调控区域中常见的同型位点聚类现象。我们观察到 TF 结合位点对之间的大量短程距离偏好，包括偏好取决于结合位点相对方向的示例。为了测试这些结合位点模式是否反映了相应 TF 之间的物理相互作用，我们分析了 27 个 TF 对，它们的结合位点表现出短距离偏好。体外蛋白质-蛋白质结合实验表明，超过 65% 的 TF 对可以直接相互作用。对于五对，我们进一步证明，如果两个位点都以首选间距存在，它们就会与 DNA 协同结合。这项研究展示了如何使用 DNA 结合基序为不同的组合 TF 作用机制生成序列特征的综合图谱。
Regulation of eukaryotic gene transcription is often combinatorial in nature, with multiple transcription factors (TFs) regulating common target genes, often through direct or indirect mutual interactions. Many individual examples of cooperative binding by directly interacting TFs have been identified, but it remains unclear how pervasive this mechanism is during animal development. Cooperative TF binding should be manifest in genomic sequences as biased arrangements of TF-binding sites. Here, we explore the extent and diversity of such arrangements related to gene regulation during Drosophila embryogenesis. We used the DNA-binding specificities of 322 TFs along with chromatin accessibility information to identify enriched spacing and orientation patterns of TF-binding site pairs. We developed a new statistical approach for this task, specifically designed to accurately assess inter-site spacing biases while accounting for the phenomenon of homotypic site clustering commonly observed in developmental regulatory regions. We observed a large number of short-range distance preferences between TF-binding site pairs, including examples where the preference depends on the relative orientation of the binding sites. To test whether these binding site patterns reflect physical interactions between the corresponding TFs, we analyzed 27 TF pairs whose binding sites exhibited short distance preferences. In vitro protein–protein binding experiments revealed that >65% of these TF pairs can directly interact with each other. For five pairs, we further demonstrate that they bind cooperatively to DNA if both sites are present with the preferred spacing. This study demonstrates how DNA-binding motifs can be used to produce a comprehensive map of sequence signatures for different mechanisms of combinatorial TF action.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
9.9
作者：
Fakhouri, Walid D.;Ay, Ahmet;Sayal, Rupinder;Dresch, Jacqueline;Dayringer, Evan;Arnosti, David N.
通讯作者：
Arnosti, David N.
影响因子：
4.5
作者：
Kaplan T;Li XY;Sabo PJ;Thomas S;Stamatoyannopoulos JA;Biggin MD;Eisen MB
通讯作者：
Eisen MB
影响因子：
11.4
作者：
Arnosti, DN;Gray, S;Levine, M
通讯作者：
Levine, M
影响因子：
10.5
作者：
Klemm, JD;Pabo, CO
通讯作者：
Pabo, CO