Transcriptional Integration of Metabolism

描述（由申请人提供）：代谢途径相互之间以及与外部环境之间错综复杂地协调，以确保小分子的正确流动，用于生物合成、能量产生和催化。许多人类病理学，糖尿病，代谢综合征和癌症是最常见的三种，与未能正确调节代谢活动有关。此外，衰老和新陈代谢是相互关联的，如热量限制在从酵母到人类的各种生物体中的影响所示。因此，更清楚地了解代谢的调节对改善人类健康和战胜疾病具有重要意义。 代谢在所有水平上受到调节，从对基因表达的转录作用到翻译后修饰环境信号。调节编码代谢酶的基因的转录允许细胞增加或降低代谢酶的水平，并提供对环境变化的更持久或更稳健的响应。 葡萄糖是所有细胞的主要能量和碳源，葡萄糖的消耗是许多代谢哺乳动物AMP活化蛋白激酶的常见触发因素，该蛋白激酶可感知各种类型的应激，包括低葡萄糖。Snf1协调转录因子和其他调节蛋白的表达和活性，这些蛋白调节在代谢途径中起作用的基因的表达，使细胞在没有葡萄糖的情况下继续生长。使用DNA微阵列的基因表达分析和使用染色质免疫沉淀的转录因子定位将识别将调节蛋白连接到特定代谢途径的途径。通过气相色谱和质谱联用对小分子的稳态水平进行代谢分析，将确定受葡萄糖耗尽时活跃的转录因子调节的未知ORF影响的代谢途径。

DESCRIPTION (provided by applicant): Metabolic pathways are intricately coordinated with each other and with the external environment to insure the correct flow of small molecules for biosynthesis, energy production, and catabolism. Many human pathologies, diabetes, metabolic syndrome, and cancer being three of the most common, are associated with the failure to correctly regulate metabolic activities. In addition, aging and metabolism are interconnected as shown by the effects of calorie restriction in organisms ranging in diversity from yeast to humans. Thus, gaining a clearer understanding of the regulation of metabolism has important implications for bettering human health and overcoming disease. Metabolism is regulated at all levels, from transcription effects on gene expression to post-translational modifying environmental signals. Regulating transcription of the genes encoding metabolic enzymes allows the cells to increase or decrease the level of metabolic enzymes and provides a longer-lasting or more robust response to environmental change. Depletion of glucose, the primary energy and carbon source for all cells, is a common trigger for many metabolic mammalian AMP-activated protein kinase that senses various types of stress, including low glucose. Snf1 coordinates the expression and activity of transcription factors and other regulatory proteins that modulate the expression of genes acting in metabolic pathways that allow the cell to continue to grow in the absence of glucose. Gene expression analysis using DNA microarrays, and transcription factor localization using chromatin immunoprecipitation, will identify the pathways connecting regulatory proteins to specific metabolic pathways. Metabolic profiling of the steady-state levels of small molecules by coupled gas chromatography and mass spectrometry will identify the metabolic pathways influenced by unknown ORFs regulated by transcription factors that are active when glucose is depleted.