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(-)/C...

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Published in:The Journal of experimental medicine Vol. 211; no. 9; p. 1821
Main Authors: Cieslak, Agata, Le Noir, Sandrine, Trinquand, Amélie, Lhermitte, Ludovic, Franchini, Don-Marc, Villarese, Patrick, Gon, Stéphanie, Bond, Jonathan, Simonin, Mathieu, Vanhille, Laurent, Vanhile, Laurent, Reimann, Christian, Verhoeyen, Els, Larghero, Jerome, Six, Emmanuelle, Spicuglia, Salvatore, André-Schmutz, Isabelle, Langerak, Anton, Nadel, Bertrand, Macintyre, Elizabeth, Payet-Bornet, Dominique, Asnafi, Vahid
Format: Journal Article
Language:English
Published: United States 25.08.2014
Subjects:
Animals
Base Sequence
Binding Sites - genetics
Cell Differentiation
Cell Line
Core Binding Factor Alpha 2 Subunit - metabolism
DNA - genetics
DNA - metabolism
Gene Rearrangement, delta-Chain T-Cell Antigen Receptor
HEK293 Cells
Homeodomain Proteins - metabolism
Humans
Kinetics
Lymphopoiesis
Mice
Molecular Sequence Data
Species Specificity
T-Lymphocyte Subsets - cytology
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
VDJ Recombinases - metabolism
ISSN:1540-9538, 1540-9538
Online Access:Get more information
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Summary: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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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20132585