Publication: RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement

Publié dans: Journal of Experimental Medicine, 2014, 211 (9), pp.1821--1832. ⟨10.1084/jem.20132585⟩

Auteurs: Agata Cieslak, Sandrine Le Noir, Amélie Trinquand, Ludovic Lhermitte, Don-Marc Franchini, Patrick Villarese, Stéphanie Gon, Jonathan Bond, Mathieu Simonin, Laurent Vanhille, Christian Reimann, Els Verhoeyen, Jérome Larghero, Emmanuelle Six, Salvatore Spicuglia, Isabelle André-Schmutz, Anton Langerak, Bertrand Nadel, Elizabeth Macintyre, Dominique Payet-Bornet, Vahid Asnafi

Résumé

V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus, Dδ2-Dδ3 rearrangements occur at a very immature thymic, CD34+/CD1a−/CD7+dim stage, before Dδ2(Dδ3)-Jδ1 rearrangements. These strictly ordered rearrangements are regulated by mechanisms acting beyond chromatin accessibility. Importantly, direct Dδ2-Jδ1 rearrangements are prohibited by a B12/23 restriction and ordered human TCR-δ gene assembly requires RUNX1 protein, which binds to the Dδ2-23RSS, interacts with RAG1, and enhances RAG1 deposition at this site. This RUNX1-mediated V(D)J recombinase targeting imposes the use of two Dδ gene segments in human TCR-δ chains. Absence of this RUNX1 binding site in the homologous mouse Dδ1-23RSS provides a molecular explanation for the lack of ordered TCR-δ gene assembly in mice and may underlie differences in early lymphoid differentiation between these species.

Lien vers Pubmed [PMID] – 25135298

Lien vers HAL – amu-01614953

Lien vers le DOI – 10.1084/jem.20132585