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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A Network Biology Approach To Aging In Yeast
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A Network Biology Approach To Aging In Yeast

机译：酵母老化的网络生物学方法

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In this study, a reverse-engineering strategy was used to infer and analyze the structure and function of an aging and glucose repressed gene regulatory network in the budding yeast Saccharo-myces cerevisiae. The method uses transcriptional perturbations to model the functional interactions between genes as a system of first-order ordinary differential equations. The resulting network model correctly identified the known interactions of key regulators in a 10-gene network from the Snf1 signaling pathway, which is required for expression of glucose-repressed genes upon calorie restriction. The majority of interactions predicted by the network model were confirmed using promoter-reporter gene fusions in gene-deletion mutants and chromatin immunoprecipitation experiments, revealing a more complex network architecture than previously appreciated. The reverse-engineered network model also predicted an unexpected role for transcriptional regulation of the SNF1 gene by hexose kinase enzyme/transcriptional repressor Hxk2, Mediator subunit Med8, and transcriptional repressor Mig1. These interactions were validated experimentally and used to design new experiments demonstrating Snf1 and its transcriptional regulators Hxk2 and Mig1 as modulators of chronological lifespan. This work demonstrates the value of using network inference methods to identify and characterize the regulators of complex phenotypes, such as aging.
机译：在这项研究中，逆向工程策略被用来推断和分析出芽的酵母酿酒酵母中的衰老和葡萄糖抑制的基因调控网络的结构和功能。该方法使用转录扰动来模拟基因之间的功能相互作用，作为一阶常微分方程组。所得的网络模型从Snf1信号传导途径正确识别了10基因网络中关键调节剂的已知相互作用，这是卡路里限制下表达葡萄糖抑制基因所必需的。使用基因缺失突变体中的启动子-报告基因融合和染色质免疫沉淀实验，证实了网络模型预测的大多数相互作用，从而揭示了比以前认识到的更为复杂的网络体系结构。反向工程网络模型还预测了己糖激酶/转录阻遏物Hxk2，介体亚基Med8和转录阻遏物Mig1对SNF1基因转录调控的意外作用。这些相互作用已通过实验验证，并用于设计新实验，证明Snf1及其转录调节子Hxk2和Mig1是时间寿命的调节剂。这项工作证明了使用网络推理方法来识别和表征复杂表型（例如衰老）的调节子的价值。

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