Oleate-responsive gene regulatory networks governing peroxisome proliferation

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DESCRIPTION (provided by applicant): Peroxisomes are dynamic, essential organelles that house numerous regulated metabolic pathways and respond dramatically to several external stimuli. Their function and biogenesis are linked to many human health concerns including neuropathologies, cancer, aging, heart disease, obesity and diabetes. In metazoans inducers of peroxisomes include fats, hypolipidemic drugs, nongenotoxic carcinogens and developmental processes. These responses are controlled at the level of transcription. As part of our long term goal of a comprehensive, quantitative understanding of how cells control peroxisome proliferation, function and biogenesis, we aim to understand transcriptional regulatory network responses to conditions that induce peroxisomes. Here, we propose a combined experimental and mathematical modeling approach focused on the transcriptional regulatory network governing the response of S. cerevisiae to oleate - a condition that induces peroxisomes. Based on results from a novel approach to the integrative analysis of genome- wide transcription factor localization and consequent gene expression data, we have generated a preliminary mathematical model of the oleate response involving four transcription factors. We propose to build on these preliminary results by additional quantitative data generation, hypothesis generation guided by the model, hypothesis testing using targeted network perturbation and analysis, and iterative model refinement and expansion. Ultimately, quantitative and predictive models of this cellular response will inform the program of peroxisome biogenesis and the principles that underlie complex gene regulatory networks that govern divergent cellular responses. PUBLIC HEALTH RELEVANCE Peroxisomes are intracellular organelles whose biogenesis and function are linked to many human concerns, including inherited neuropathologies, aging, cancer, heart disease, obesity and diabetes. Moreover, the size, number and content of peroxisomes in a cell are regulated and can change dramatically in response to factors such as fats, hypolipidemic drugs, carcinogens and cell differentiation. Understanding peroxisome dynamics, biogenesis and function are critical to understanding these numerous human conditions and to their future treatment.