Régions régulatrices Eµ et 3'RR au locus des chaînes lourdes d'immunoglobulines : dynamique, fonctions et interactions des modules

Abstract : Immunoglobulin (Ig) gene expression in B cells depends on multiple genetic rearrangements named V(D)J recombination, class switch recombination (CSR) and somatic hypermutation (SHM). These events are controlled by cis-regulatory elements which are, especially numerous within the IgH locus. Major IgH regulatory elements are Eµ composed of a core enhancer flanked by nuclear matrix attachment regions MARsEµ and the regulatory region located at the 3’end of the locus (3’RR), composed of 4 enhancers (hs3a; hs1-2; hs3b; hs4) harbouring a highly conserved quasi-palindromic structure. To study these regulatory regions, we analyzed multiple mice models carrying endogenous deletions of either the entire Eµ region, MARsEµ only or various parts of the 3’RR. These models revealed unsuspected functions for all IgH regulatory regions, at various stages of B cell development. Beyond its role to control accessibility prior DH to JH rearrangements, we identified the window of activity for Eµ region and its particular role on transcription and expression of the µ heavy chain from pre-B to the transitional stages. Indeed, the Eµ enhancer modulates pre-BCR and BCR expression and consequently modulates the mature B cell fate toward marginal zone and follicular compartments. Our study also indicated that the absence of Eµ has no effect on VH segment usage during V to DJ recombination. We also showed that MARsEµ are implicated in the targeting of Ig genes by SHM. The mechanism by which MARsEµ enhances SHM remains to be clarified but we showed that the process does not depend on transcription. Surprisingly MARsEµ also modulates SHM occuring on genes located on different chromosomes: the Ig light chain loci (Igκ) and AID off-targets loci (Bcl6 and Cd83).In a study comparing a new mouse model devoid of the 3’ IgH quasi-palindromic region (hs3a to hs3b) to previous relevant models available in our laboratory (3’RR KO and hs3b-hs4 KO), we identified two complementary functional modules within the 3’RR. The distal module (hs4), which regulates Ig heavy chain expression (and therefore BCR expression) from the immature to mature naïve B cell stages and the proximal module (hs3a to hs3b and its quasi-palindromic structure) required at mature stages for SHM, CSR to most isotypes in activated B cells, and antibody production in plasma cells.
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Armand Garot. Régions régulatrices Eµ et 3'RR au locus des chaînes lourdes d'immunoglobulines : dynamique, fonctions et interactions des modules. Médecine humaine et pathologie. Université de Limoges, 2015. Français. ⟨NNT : 2015LIMO0054⟩. ⟨tel-01649212⟩

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