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Modélisation multi-échelles de réseaux biologiques pour l’ingénierie métabolique d'un châssis biotechnologique

Abstract : Metabolism defines the set of biochemical reactions within an organism, allowing it to survive and adapt to different environments. Regulating these reactions requires complex processes involving many effectors interacting together at different scales.Developing models of these regulatory networks is therefore an essential step in better understanding the precise mechanisms governing living systems and ultimately enabling the design of synthetic, self-regulating and adaptive systems at the genome level. As part of this interdisciplinary work, we propose to use an iterative network inference and interrogation approach to guide the engineering of the metabolism of the yeast of industrial interest Yarrowia lipolytica.Based on transcriptomic data, the first network for the regulation of adaptation to nitrogen limitation and lipid production in this yeast was inferred.The interrogation of this network has then allowed to to highlight and experimentally validate the impact of several regulators on lipid accumulation. In order to further explore the relationships between regulation and metabolism, a new method, CoRegFlux, has been proposed for the prediction of metabolic phenotype based on the influence profiles of regulators in the studied conditions. This R package, available on the Bioconductor platform, was then used to better understand adaptation to nitrogen limitation and to identify phenotypes of interest for strain engineering, particularly for the production of lipids and amino acid derivatives such as violacein.Thus, through an iterative approach, this work provides new insights into the interactions between regulation and metabolism in Y. lipolytica, conserved regulatory module in this yeast and contributes to the development of innovative integrative methods for computer-assisted strain design.
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Submitted on : Wednesday, November 27, 2019 - 5:25:09 PM
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Pauline Trebulle. Modélisation multi-échelles de réseaux biologiques pour l’ingénierie métabolique d'un châssis biotechnologique. Biotechnologies. Université Paris Saclay (COmUE), 2019. Français. ⟨NNT : 2019SACLA022⟩. ⟨tel-02383469⟩

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