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, Plusieurs études incluant celles menées au laboratoire ont montré que ces allèles non-productifs sont transcrits mais subissent une régulation post-transcriptionnelle impliquant le mécanisme de dégradation des ARNm appelé NMD « Nonsense-Mediated mRNA Decay ». Cette surveillance ARN diminue ainsi le taux d'ARNm codant pour des chaînes d'Ig tronquées. En revanche, l'impact de l'épissage alternatif des transcrits d'Ig non-productifs sur la production d'Ig aberrantes reste jusqu'ici peu exploré. L'étude de ce processus appelé NAS (« Nonsense-associated Altered Splicing, Résumé Le processus aléatoire des recombinaisons V(D)J permet d'obtenir un répertoire d'anticorps (Ac) ou immunoglobulines (Ig) hautement diversifié
, Ce phénomène nommé TIE-checkpoint (Truncated-Ig Exclusion) conduisant à l'élimination des plasmocytes exprimant des Ig tronquées, est la conséquence d'un saut d'exon lors de l'épissage des transcrits Ig? non-productifs. Pour étudier les évènements de NAS lors de l'épissage des transcrits d'Ig dans les plasmocytes, il faut par conséquent limiter l'activation du TIE-checkpoint. A l'aide d'un modèle murin présentant un exon non-sens additionnel au locus IgH, Les projets développés lors de cette thèse ont révélé la toxicité des chaînes d'Ig dépourvues de domaine variable (V) dans les plasmocytes
, Cette étude a été menée dans des cellules B primaires et des plasmocytes. Les résultats obtenus ont révélé que l'hypertranscription des gènes d'Ig, qui accompagne la différenciation plasmocytaire, favorise l'épissage alternatif des transcrits d'Ig non-productifs
, Nous avons également étudié les éventuelles connexions entre le mécanisme de NMD, impliqué dans la surveillance des ARNm, et l'UPR (« Unfolded Protein Response ») permettant de réguler l'homéostasie protéique dans les plasmocytes. De façon originale, nous avons identifié une boucle de régulation positive entre les processus de surveillance ARN (NMD)
, La mise en évidence de cette coopération dans les plasmocytes constitue un exemple unique au vue de la littérature et, aurait pour effet de limiter la synthèse d'Ig tronquées tout en autorisant la synthèse massive d
, Cette étude a apporté des précisions sur le rôle des sites donneurs d'épissage des exons I et révélé que la reconnaissance de ces sites d'épissage module l'intensité de la transcription de la région « switch » S adjacente, et par conséquent, son accessibilité à AID « Activation-Induced cytidine Deaminase » lors de la CSR, nous avons étudié le rôle de l'épissage des transcrits d'Ig non-codants (appelés transcrits I « germinaux ») au cours du processus de CSR « Class Switch Recombination