RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement
The Journal of Experimental Medicine , Volume 211 - Issue 9 p. 1821- 1832
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.
|The Journal of Experimental Medicine|
|Organisation||Department of Immunology|
Cieslak, A, le Noir, S, Trinquand, A, Lhermitte, L, Franchini, D.-M, Villarese, P, … Asnafi, V. (2014). RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement. The Journal of Experimental Medicine, 211(9), 1821–1832. doi:10.1084/jem.20132585