RUNX1-dependent RAG1 deposition instigates human TCR-? 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-?/? locus, D?2-D?3 rearrangements occur at a very immature thymic, CD34(+)/CD1a(-)/CD7(+dim) stage, before D?2(D?3)-J?1 rearrangements. These strictly ordered rearrangements are regulated by mechanisms acting beyond chromatin accessibility. Importantly, direct D?2-J?1 rearrangements are prohibited by a B12/23 restriction and ordered human TCR-? gene assembly requires RUNX1 protein, which binds to the D?2-23RSS, interacts with RAG1, and enhances RAG1 deposition at this site. This RUNX1-mediated V(D)J recombinase targeting imposes the use of two D? gene segments in human TCR-? chains. Absence of this RUNX1 binding site in the homologous mouse D?1-23RSS provides a molecular explanation for the lack of ordered TCR-? gene assembly in mice and may underlie differences in early lymphoid differentiation between these species.

SUBMITTER: Cieslak A 

PROVIDER: S-EPMC4144731 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature