RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement.
J Exp Med
; 211(9): 1821-32, 2014 Aug 25.
Article
em En
| MEDLINE
| ID: mdl-25135298
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Subpopulações de Linfócitos T
/
Rearranjo Gênico da Cadeia delta dos Receptores de Antígenos dos Linfócitos T
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Proteínas de Homeodomínio
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Subunidade alfa 2 de Fator de Ligação ao Core
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2014
Tipo de documento:
Article