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

authors

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

document type

abstract

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.

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