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Rôle de la stochasticité de l’expression des gènes dans les processus de différenciation

Abstract : This study aims on cell making-decision mechanisms in metazoan cells, in relation with stochastic gene expression SGE. Our hypothesis is that SGE favors cell making-decision to differentiate. If one sees differentiation from the point of view of dynamical systems theory, self-renewing cells and differentiated cells are in "attractor" states, such as valleys, separated by a hill, in an epigenetic landscape. The shape of this landscape is the result of the gene regulatory network state. To differentiate, cells have to escape from this self-renewal state to transit through the hill and to attain the differentiated state. SGE could activate cell decision-making to differentiate by controlling the landscape shape via the gene regulatory network. Results presented here support this hypothesis. Using single cell transcriptomic data, we observed a surge in SGE during erythropoiesis before irreversible cell commitment. Using the same data, a gene regulatory network was inferred by WASABI, a dedicated algorithm, looking for molecular mechanisms behind differentiation. By experimentally modifying SGE level in cells using drugs, we demonstrated the causative role of SGE in erythroid differentiation. We also showed that these drugs have an effect on muscular differentiation, supporting the generality of this link between SGE and differentiation. Finally, we explored a new dynamical point of view on chronic myeloid leukemia cells and showed the existence of subpopulations in leukemic cells that could be the source of treatment resistance. All these results suggest that to make decision, cells use cell-to-cell heterogeneity, allowing the activation of processes, such as differentiation
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Anissa Guillemin. Rôle de la stochasticité de l’expression des gènes dans les processus de différenciation. Biologie cellulaire. Université de Lyon, 2018. Français. ⟨NNT : 2018LYSE1188⟩. ⟨tel-01950418⟩

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