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

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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https://hal-amu.archives-ouvertes.fr/hal-01614953
Contributor : Lionel Spinelli <>
Submitted on : Wednesday, October 11, 2017 - 4:49:30 PM
Last modification on : Thursday, April 9, 2020 - 11:53:32 AM

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

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