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The elucidation of the nuclear receptor gene regulatory network in mouse microglia

Final Report Summary - MNRGN (The elucidation of the nuclear receptor gene regulatory network in mouse microglia)

A summary description of the project objectives:
This project aims to improve our understanding regarding the structural and dynamic properties of gene regulatory networks (GRNs) underlying distinct biological processes. As a model system, we originally chose microglia because they constitute a readily accessible and relatively homogeneous cellular system in which the transcriptional mechanisms underlying its biological function are currently poorly understood. However and as clearly stipulated in the first period report, we switched our focus to characterizing the GRNs underlying fat cell differentiation because of practical and ethical issues (i.e. many mice would have to be sacrificed to generate a primary microglial cell culture). We reasoned that this is a valid alternative because studying adipogenesis also has clear, medical relevance, because well-established in vitro adipogenic models are available, and finally because adipogenesis occurs through a cascade of gene expression events, which are mediated by GRNs. Elucidating their content and dynamic properties is therefore essential. Thus, although the specific biological system was altered (and approved by the Commission), the overall scientific philosophy and structure of the grant remained intact, i.e. to determine the temporal gene expression profiles of transcription factors (TFs) during a biological process (now fat cell differentiation), to locate regulatory elements involved in this process, to map interactions between TFs and uncovered regulatory elements, and finally to identify and characterize critical adipogenic TFs. To perform these experiments, we proposed to develop a mouse-specific, gene-centered protein-DNA interaction screening method, and to implement genome-wide techniques to validate some of the detected interactions. Together, we reasoned that the obtained knowledge may provide an experimental and data framework for future modeling efforts to make predictions on how adipogenic GRNs behave under different physiological or pathological conditions, or on how to manipulate these networks such that excessive adipocyte accumulation and its deleterious consequences can be prevented or suppressed. Thus, given the well-established relationship between excess fat mass and the metabolic syndrome as well as cancer, this work may not only support important technical advances and generate resources and data of interest to the scientific community at large, it may also significantly increase our understanding of the molecular mechanisms underlying these pathologies.

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