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

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.
Mesh Terms:
Animals, Base Sequence, Binding Sites, Cell Differentiation, Cell Line, Core Binding Factor Alpha 2 Subunit, DNA, Gene Rearrangement, delta-Chain T-Cell Antigen Receptor, HEK293 Cells, Homeodomain Proteins, Humans, Kinetics, Lymphopoiesis, Mice, Molecular Sequence Data, Species Specificity, T-Lymphocyte Subsets, VDJ Recombinases
J. Exp. Med.
Date: Aug. 25, 2014
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