A quantitative model of transcriptional regulation reveals the influence of binding location on expression.
A quantitative model of transcriptional regulation reveals the influence of binding location on expression.
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DOI：
10.1371/journal.pcbi.1000773
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发表时间：
2010-04-29
影响因子：
4.3
通讯作者：
Fraenkel E
中科院分区：
文献类型：
--
作者：
MacIsaac KD;Lo KA;Gordon W;Motola S;Mazor T;Fraenkel E
自分子生物学诞生以来，了解转录调控的机制基础一直是分子生物学的中心焦点。新的高通量染色质免疫沉淀实验表明，大多数调节蛋白结合哺乳动物基因组中的数千个位点。然而，这些结合位点的功能意义仍不清楚。我们提出了转录调控的定量模型，表明每个结合位点对组织特异性基因表达的贡献很大程度上取决于其相对于转录起始位点的位置。对于三种细胞类型，我们表明，通过考虑结合位置，可以预测细胞类型之间的相对表达水平，其准确度接近不同实验平台之间的一致性水平。我们的模型表明，对于这些细胞类型中分析的转录因子，调节位点对表达的影响在 10 kilobase 范围内随着距转录起始位点的距离几乎呈线性下降。与进化保守和非保守序列的结合对转录调控有显着贡献。我们的方法还揭示了单个蛋白质在激活或抑制转录中的定量、组织特异性作用。这些结果表明，调节器结合位置在影响表达方面发挥着以前未被认识到的作用，并且模糊了近端启动子和远端结合事件之间的经典区别。基因表达在很大程度上是由称为转录因子的调节蛋白控制的，这些蛋白结合基因组中的特定位点。分子生物学的一个主要焦点是了解这些转录因子如何与细胞的转录机制、基因组相互作用，以及如何相互作用以在各种生理环境下打开和关闭基因的表达。以前的转录调控建模方法主要集中在调控位点转录因子组之间复杂的组合相互作用，或单个蛋白质的特定激活或抑制功能。在这项工作中，我们提出了一个新的建模框架，并证明在预测调控位点对基因表达的影响时，同样重要且之前被忽视的考虑因素就是其相对于附近基因转录起始位点的位置。我们的结果表明，一般来说，结合事件距离基因的转录起始位点越近，它对表达的影响就越大。我们还表明，考虑在调控位点结合的特定蛋白质有助于预测附近基因的表达。然而，考虑这些位点的序列保守水平并不能带来更准确的预测。
Understanding the mechanistic basis of transcriptional regulation has been a central focus of molecular biology since its inception. New high-throughput chromatin immunoprecipitation experiments have revealed that most regulatory proteins bind thousands of sites in mammalian genomes. However, the functional significance of these binding sites remains unclear. We present a quantitative model of transcriptional regulation that suggests the contribution of each binding site to tissue-specific gene expression depends strongly on its position relative to the transcription start site. For three cell types, we show that, by considering binding position, it is possible to predict relative expression levels between cell types with an accuracy approaching the level of agreement between different experimental platforms. Our model suggests that, for the transcription factors profiled in these cell types, a regulatory site's influence on expression falls off almost linearly with distance from the transcription start site in a 10 kilobase range. Binding to both evolutionarily conserved and non-conserved sequences contributes significantly to transcriptional regulation. Our approach also reveals the quantitative, tissue-specific role of individual proteins in activating or repressing transcription. These results suggest that regulator binding position plays a previously unappreciated role in influencing expression and blurs the classical distinction between proximal promoter and distal binding events. Gene expression is controlled, in large part, by regulatory proteins called transcription factors that bind specific sites in the genome. A major focus of molecular biology has been understanding how these transcription factors interact with the cell's transcriptional machinery, the genome, and with each other to turn genes' expression on and off in various physiological contexts. Previous approaches for modeling transcriptional regulation have focused on the complex combinatorial interactions between groups of transcription factors at regulatory sites, or on the specific activating or repressive functions of individual proteins. In this work, we present a new modeling framework and demonstrate that an equally important, and previously overlooked, consideration in predicting the effect that a regulatory site has on gene expression is simply its location relative to the transcription start site of nearby genes. Our results show that, in general, the closer a binding event is to a gene's transcription start site, the more it influences expression. We also show that considering the particular proteins bound at a regulatory site helps predict the expression of nearby genes. However, considering the sequence conservation level of these sites does not lead to more accurate predictions.
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影响因子：
64.5
作者：
An, W;Kim, J;Roeder, RG
通讯作者：
Roeder, RG
人肝细胞中的核心转录调节电路。
影响因子：
9.9
作者：
通讯作者：
--
影响因子：
9.8
作者：
Li XY;MacArthur S;Bourgon R;Nix D;Pollard DA;Iyer VN;Hechmer A;Simirenko L;Stapleton M;Luengo Hendriks CL;Chu HC;Ogawa N;Inwood W;Sementchenko V;Beaton A;Weiszmann R;Celniker SE;Knowles DW;Gingeras T;Speed TP;Eisen MB;Biggin MD
通讯作者：
Biggin MD
影响因子：
5.7
作者：
Eilers, PHC;Marx, BD
通讯作者：
Marx, BD
影响因子：
56.9
作者：
MAIRE, P;WUARIN, J;SCHIBLER, U
通讯作者：
SCHIBLER, U