Etude du rôle de la région régulatrice en 3' du locus IgH au cours du développement lymphocytaire B normal et pathologique

Abstract : During B-cell development, the heavy chains locus (IgH) undergoes three genic rearrangement events. During the early stages, before encountering the antigen, VDJ rearrangements allow the generation of a functional Ig repertoire. During the late stages, somatic hypermutation (SHM) increases the affinity of the Ig for its antigen, while class switch recombination (CSR) modifies its effector functions. These events imply thegeneration of potentially oncogenic DNA lesions, and thus require a strict regulation. This regulation is assured by several cis-regulatory elements spread along the IgH locus, including the 3’ regulatory region (3’RR). The 3’RR extends on more than 30kb and contains four transcriptional enhancers, the first three displaying a palindromic conformation. During my PhD, I investigated several mouse models carrying deletion of part or totality of the 3’RR to investigate its role during B cell development. We demonstrated how she precisely regulates CSR by specifically targeting the acceptor switch region, and described the poorly known mechanism of CSR toward IgD. Otherwise, we have demonstrated its importance during SHM and in the correct development of the different B cell subpopulations. Finally, by comparing the results obtained during the analysis of the various mouse models, we have demonstrated that the palindromic structure of the 3’RR is required for optimal SHM, but not for CSR.
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Alexis Saintamand. Etude du rôle de la région régulatrice en 3' du locus IgH au cours du développement lymphocytaire B normal et pathologique. Médecine humaine et pathologie. Université de Limoges, 2016. Français. ⟨NNT : 2016LIMO0007⟩. ⟨tel-01306682⟩

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