RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement - Aix-Marseille Université Access content directly
Journal Articles Journal of Experimental Medicine Year : 2014

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

Sandrine Le Noir
Don-Marc Franchini
  • Function : Author
Patrick Villarese
  • Function : Author
Stéphanie Gon
Mathieu Simonin
  • Function : Author
Christian Reimann
  • Function : Author
Els Verhoeyen
  • Function : Author
Jérome Larghero
  • Function : Author
Emmanuelle Six
Isabelle André-Schmutz
Anton Langerak

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.

Dates and versions

hal-01614953 , version 1 (11-10-2017)

Identifiers

Cite

Agata Cieslak, Sandrine Le Noir, Amélie Trinquand, Ludovic Lhermitte, Don-Marc Franchini, et al.. RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement. Journal of Experimental Medicine, 2014, 211 (9), pp.1821--1832. ⟨10.1084/jem.20132585⟩. ⟨hal-01614953⟩
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