Transcriptional Integration of Metabolism

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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.