Modular combinatorial binding among human trans-acting factors reveals direct and indirect factor binding.
Modular combinatorial binding among human trans-acting factors reveals direct and indirect factor binding.
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DOI：
10.1186/s12864-016-3434-3
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发表时间：
2017-01-06
期刊：
影响因子：
4.4
通讯作者：
Gifford DK
中科院分区：
文献类型：
--
作者：
Guo Y;Gifford DK
反式作用因子（trans-acting factors，TF）与DNA的结合对基因调控的时空特异性至关重要。对于某些调控区域，组合一个以上的调控模块（结合在一起的TF组）以实现环境特异性基因调控。然而，以前的方法限于成对TF共关联分析或假设每个调控区中仅使用一个模块。我们提出了一种新的计算方法，模型TF组合绑定的模块化组织。我们的方法使用主题模型从体内结合数据中学习紧凑和连贯的调控模块。我们发现K562细胞中115个TF的结合可以被组织成49个可解释的模块。此外，我们发现成千上万的调控区域使用多个模块，这是以前基于硬聚类的方法无法观察到的结构。发现的模块概括了许多已发表的蛋白质-蛋白质物理相互作用，具有染色质状态的一致功能注释，并揭示了背景特异性共结合，例如NFY + FOS + SP的基因近端结合和NFY + FOS + USF的远端结合。对于某些TF，直接结合（存在基序）的共结合配偶体不同于间接结合（不存在基序）的共结合配偶体;不同的共结合配偶体组可以预测TF是直接结合还是间接结合，准确度高达95%。跨两种细胞类型的联合分析揭示了细胞类型特异性和共享的调控模块。我们的研究结果提供了全面的细胞类型特异性组合结合图，并提出了一个模块化的组织组合结合。本文的在线版本（doi：10.1186/s12864-016-3434-3）包含补充材料，可供授权用户使用。
The combinatorial binding of trans-acting factors (TFs) to the DNA is critical to the spatial and temporal specificity of gene regulation. For certain regulatory regions, more than one regulatory module (set of TFs that bind together) are combined to achieve context-specific gene regulation. However, previous approaches are limited to either pairwise TF co-association analysis or assuming that only one module is used in each regulatory region. We present a new computational approach that models the modular organization of TF combinatorial binding. Our method learns compact and coherent regulatory modules from in vivo binding data using a topic model. We found that the binding of 115 TFs in K562 cells can be organized into 49 interpretable modules. Furthermore, we found that tens of thousands of regulatory regions use multiple modules, a structure that cannot be observed with previous hard clustering based methods. The modules discovered recapitulate many published protein-protein physical interactions, have consistent functional annotations of chromatin states, and uncover context specific co-binding such as gene proximal binding of NFY + FOS + SP and distal binding of NFY + FOS + USF. For certain TFs, the co-binding partners of direct binding (motif present) differs from those of indirect binding (motif absent); the distinct set of co-binding partners can predict whether the TF binds directly or indirectly with up to 95% accuracy. Joint analysis across two cell types reveals both cell-type-specific and shared regulatory modules. Our results provide comprehensive cell-type-specific combinatorial binding maps and suggest a modular organization of combinatorial binding. The online version of this article (doi:10.1186/s12864-016-3434-3) contains supplementary material, which is available to authorized users.
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