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Characterization of the Lysine Acetyltransferase dmMOZ function and mode of action during Drosophila hematopoiesis

Abstract : Hematopoiesis is a very tightly regulated process leading to the normal production of every blood cells in an organism. In mammals there is a lot of cell types that participate to the establishment of the defense mechanisms of the body. All those cells come from the terminal differentiation of a single cell called Hematopoietic Stem Cell (HSC) which will differentiate to give rise to committed progenitors that will eventually differentiate all blood cell types. HSCs are among the most controlled cells in the organism. Indeed, deregulation of their normal function (excessive proliferation, premature differentiation, ...) can be at the onset of severe blood pathologies called leukemias. Several molecular factors are involved in HSC regulation, and some of them, like RUNX1 and the Monocytic Leukemia Zinc-Finger protein (MOZ), are targets of mutations or chromosomal rearrangements that lead to a leukemic transformation. In Drosophila, blood cells share functional homology with the mammalian myeloid lineage, and the molecular actors controlling their formation are well conserved. Indeed, differentiation of crystal cells (CC), which have similar functions than megakaryocytes, occurs following the interaction of RUNX1 homolog, Lozenge (Lz) and GATA1 Serpent (Srp). With the aim at identifying regulators of Srp/Lz transcriptional activity, a genome-wide screen led by my team allowed the identification of enoki mushroom (enok) as a strong negative regulator of this activity. Enok is the homolog of MOZ in Drosophila, and a preliminary study in vivo showed that Enok is essential for CC development during the larval stage, as CC almost completely disappear in enok loss of function context. The objective of my PhD was to understand the mechanisms by which Enok regulates CC formation in the Drosophila larvae. During the larval stage, CC are generated by the transdifferentiation of macrophages, after their activation by the Notch signaling pathway and onset of Lz expression. In contrast to data published by another group, I demonstrated that Lz is required and sufficient to initiate the expression of the Hippo signaling pathway effector Yorkie, and not the contrary. Furthermore, using loss of function and rescue experiments, I showed that Enok is absolutely required cell autonomously in CC precursors for Lz expression but not for the proper Notch signaling which appears normal in an enok mutant context.[...]
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Thomas Genais. Characterization of the Lysine Acetyltransferase dmMOZ function and mode of action during Drosophila hematopoiesis. Genetics. Université Paul Sabatier - Toulouse III, 2019. English. ⟨NNT : 2019TOU30215⟩. ⟨tel-02934289⟩

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