Functional genomics of the dynamic molecular network controlling mRNA translation and decay

摘要 细胞对环境变化和压力的反应是通过调节翻译和衰变 细胞质中的mRNA。这种转录后调节对于维持正常的细胞生长至关重要。 细胞生理学通常，这些调节程序保护细胞免受病理压力。在 然而，在其他情况下，适应不良反应是疾病表型的基础。理解 这些动态的、对环境敏感的转录后调节程序是至关重要的， 了解细胞生理学，并承诺新的治疗目标，以支持保护性 抑制有害的反应。 最近的工作已经编目了数百种mRNA结合蛋白。我们了解如何 这些蛋白质影响它们所结合的mRNA， 蛋白质，我们通常缺乏对它们在细胞中更广泛作用的理解。我们的激励 假设这些蛋白质中有许多靶向特定的转录物并调节其翻译 以及响应环境和细胞内线索的协调方式的稳定性。 事实上，我们知道有一些调节蛋白能与编码功能相关基因的转录本结合 并在促进衰变或促进翻译之间切换，以响应调节性的 磷酸化我们认为，这是一种更为普遍的模式。 该提案的广泛科学目标是阐明后- 细胞中的转录调控。我们将采用高通量和无偏见的方法， 从mRNA结合蛋白向外工作，以识别控制其功能的信号。 活动，调节其影响的上游和下游因素，以及调节 他们控制的程序。我们的工作将揭示如何以及为什么 基因表达是转录后控制的。我们还将制定方法， 转移到其他生物系统中来解决这个问题。

ABSTRACT Cells respond to environmental changes and stresses by modulating the translation and decay of mRNAs in the cytosol. This post-transcriptional regulation is critical for maintaining proper cellular physiology. Often, these regulatory programs protect cells from pathological stresses. In other cases, however, maladaptive responses underlie disease phenotypes. Understanding these dynamic, environmentally responsive post-transcriptional regulatory programs is critical for understanding cell physiology and promises novel therapeutic targets to support protective responses and suppress damaging ones. Recent work has catalogued hundreds of mRNA-binding proteins. Our understanding of how these proteins affect the mRNAs they bind has lagged behind studies that enumerate these proteins, and we generally lack an understanding of their broader role in the cell. Our motivating hypothesis is that many of these proteins target specific transcripts and regulate their translation and stability in a coordinated fashion in response to environmental and intracellular cues. Indeed, we know of regulatory proteins that bind transcripts encoding functionally related genes and switch between promoting decay or promoting translation in response to regulatory phosphorylation. We believe that this represents a more widespread model. The broad scientific goal of this proposal is to elucidate the functional networks of post- transcriptional regulation in the cell. We will apply high-throughput and unbiased approaches to work outward from mRNA-binding proteins in order to identify the signals that control their activity, the upstream and downstream factors that mediate their effect, and the regulatory programs that they control. Our work will reveal the general principles governing how and why gene expression is controlled post-transcriptionally. We will also develop approaches that can be transferred to address this question in a wide array of other biological systems.