Divergence in DNA Specificity among Paralogous Transcription Factors Contributes to Their Differential In Vivo Binding.
Divergence in DNA Specificity among Paralogous Transcription Factors Contributes to Their Differential In Vivo Binding.
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DOI：
10.1016/j.cels.2018.02.009
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发表时间：
2018-04-25
期刊：
影响因子：
9.3
通讯作者：
Gordan R
中科院分区：
文献类型：
--
作者：
Shen N;Zhao J;Schipper JL;Zhang Y;Bepler T;Leehr D;Bradley J;Horton J;Lapp H;Gordan R
类似转录因子(TF)经常被报道具有相同的DNA结合基序，尽管它们执行不同的调节功能。基因组靶向的差异通常被认为是由于与蛋白质辅助因子或染色质环境的相互作用。使用一个名为iMADS(差异特异性的整合建模和分析)的计算-实验框架，我们表明，与先前的假设相反，平行的TF即使在体外也以不同的方式与基因组靶点结合。我们使用iMADS对来自4个蛋白质家族的11个转录因子的特异性差异进行了量化、建模和分析。我们发现，平行的转录因子主要在中亲和力和低亲和力位点发生分歧，目前的基序模型很难捕捉到这些位点。我们识别了相似TF不同偏好的序列和形状特征，并表明平行TF在特异性上的内在差异导致了它们在体内的不同结合。因此，我们的研究代表着在破译TF家族不同特异性的分子机制方面向前迈进了一步。简而言之，本研究介绍了iMADS，这是一个用于量化、建模和分析同源转录因子的DNA结合偏好的通用框架。与人们预期的Paralog结合相同的DNA基序相反，iMADS表明它们喜欢不同的DNA序列和DNAshape特征。这种特异性上的差异有助于体内结合的差异，并且在中等和低亲和力部位最为明显，而标准的DNA基序模型不能捕捉到这些部位。
Paralogous transcription factors (TFs) are oftentimes reported to have identical DNA-binding motifs, despite the fact that they perform distinct regulatory functions. Differential genomic targeting by paralogous TFs is generally assumed to be due to interactions with protein co-factors or the chromatin environment. Using a computational-experimental framework called iMADS (integrative modeling and analysis of differential specificity), we show that, contrary to previous assumptions, paralogous TFs bind differently to genomic target sites even in vitro. We used iMADS to quantify, model, and analyze specificity differences between 11 TFs from 4 protein families. We found that paralogous TFs have diverged mainly at mediumand low-affinity sites, which are poorly captured by current motif models. We identify sequence and shape features differentially preferred by paralogous TFs, and we show that the intrinsic differences in specificity among paralogous TFs contribute to their differential in vivo binding. Thus, our study represents a step forward in deciphering the molecular mechanisms of differential specificity in TF families. In Brief: This study introduces iMADS, a general framework to quantify, model, and analyze the DNA-binding preferences of paralogous transcription factors. Contrary to the expectation that paralogs bind to identical DNA motifs, iMADS demonstrates that they prefer different DNA-sequence and DNAshape features. This divergence in specificity contributes to differential in vivo binding, and it is most pronounced at mediumand low-affinity sites, which are not captured by standard DNA-motif models.
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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Bulyk ML
影响因子：
3.7
作者：
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通讯作者：
Nykter M
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DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
通讯作者：
de Hoon MJ
影响因子：
4.3
作者：
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通讯作者：
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影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
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