MC EMiNEM maps the interaction landscape of the Mediator.
MC EMiNEM maps the interaction landscape of the Mediator.
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DOI：
10.1371/journal.pcbi.1002568
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发表时间：
2012
影响因子：
4.3
通讯作者：
Tresch A
中科院分区：
文献类型：
--
作者：
Niederberger T;Etzold S;Lidschreiber M;Maier KC;Martin DE;Fröhlich H;Cramer P;Tresch A
介体是一种高度保守的大型多蛋白复合物，主要参与真核生物mRNA转录的调控。它作为一种通用的转录因子，通过整合来自基因特异性激活物或阻遏物的调节信号到RNA聚合酶II。传递这些信号的中介子亚基之间的内部相互作用网络在很大程度上是未知的。在这里，我们介绍MC EMiNEM，一种新的方法，用于检索对mRNA转录具有多效性的蛋白质之间的功能依赖性。MC EMiNEM基于嵌套效应模型（NEM），NEM是一类扩展了层次聚类思想的概率图模型。与现有方法相比，它将跳模蒙特卡罗（MC）采样与NEM的期望最大化（EM）算法相结合，以提高灵敏度。对酿酒酵母中的四个介体扰动研究进行的荟萃分析，其中三个未发表，为介体信号网络提供了新的见解。除了已知的中介子单元的模块化组织之外，MC EMiNEM还揭示了其内部信息流的层次顺序，这些信息流通过复合体内的结构变化进行传递。我们确定的N-末端Med 7作为一个外围实体，只需要局部结构的变化扰动后，而C-末端Med 7和Med 19似乎发挥了核心作用。MC EMiNEM将介体亚基与最直接受影响的基因相关联，结合基因集富集分析，使我们能够构建介体亚基和转录因子的相互作用图谱。在遗传上相同的细胞中，表型多样性和环境适应是通过精确调节其转录程序来实现的。这是一个具有挑战性的任务，解开部分复杂的网络涉及基因调控成分和它们的相互作用。在这里，我们阐明了介体复合物在酵母转录调控中的作用。介体在所有真核生物中高度保守，并作为基因特异性转录因子和一般mRNA转录机制之间的界面。尽管大多数涉及的蛋白质和众多的结构特征是已知的，但其对基础转录和激活转录的功能贡献的细节仍然模糊不清。我们使用基因表达数据，测量后扰动的各种调解子亚基，涉及调解结构的方式，它处理监管信息。此外，我们将特定的亚基与相互作用的转录因子联系起来。
The Mediator is a highly conserved, large multiprotein complex that is involved essentially in the regulation of eukaryotic mRNA transcription. It acts as a general transcription factor by integrating regulatory signals from gene-specific activators or repressors to the RNA Polymerase II. The internal network of interactions between Mediator subunits that conveys these signals is largely unknown. Here, we introduce MC EMiNEM, a novel method for the retrieval of functional dependencies between proteins that have pleiotropic effects on mRNA transcription. MC EMiNEM is based on Nested Effects Models (NEMs), a class of probabilistic graphical models that extends the idea of hierarchical clustering. It combines mode-hopping Monte Carlo (MC) sampling with an Expectation-Maximization (EM) algorithm for NEMs to increase sensitivity compared to existing methods. A meta-analysis of four Mediator perturbation studies in Saccharomyces cerevisiae, three of which are unpublished, provides new insight into the Mediator signaling network. In addition to the known modular organization of the Mediator subunits, MC EMiNEM reveals a hierarchical ordering of its internal information flow, which is putatively transmitted through structural changes within the complex. We identify the N-terminus of Med7 as a peripheral entity, entailing only local structural changes upon perturbation, while the C-terminus of Med7 and Med19 appear to play a central role. MC EMiNEM associates Mediator subunits to most directly affected genes, which, in conjunction with gene set enrichment analysis, allows us to construct an interaction map of Mediator subunits and transcription factors. Phenotypic diversity and environmental adaptation in genetically identical cells is achieved by an exact tuning of their transcriptional program. It is a challenging task to unravel parts of the complex network of involved gene regulatory components and their interactions. Here, we shed light on the role of the Mediator complex in transcription regulation in yeast. The Mediator is highly conserved in all eukaryotes and acts as an interface between gene-specific transcription factors and the general mRNA transcription machinery. Even though most of the involved proteins and numerous structural features are already known, details on its functional contribution on basal as well as on activated transcription remain obscure. We use gene expression data, measured upon perturbations of various Mediator subunits, to relate the Mediator structure to the way it processes regulatory information. Moreover, we relate specific subunits to interacting transcription factors.
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影响因子：
7.3
作者：
Conaway, Ronald C.;Conaway, Joan Weliky
通讯作者：
Conaway, Joan Weliky
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
1.7
作者：
Froehlich, Holger;Tresch, Achim;Beissbarth, Tim
通讯作者：
Beissbarth, Tim
DOI：
10.1111/j.2517-6161.1977.tb01600.x
发表时间：
1977-01-01
期刊：
JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-METHODOLOGICAL
影响因子：
--
作者：
DEMPSTER, AP;LAIRD, NM;RUBIN, DB
通讯作者：
RUBIN, DB
影响因子：
64.5
作者：
Holstege, FCP;Jennings, EG;Young, RA
通讯作者：
Young, RA