RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement-Reference-Cited by-同舟云学术

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

Published:2014-08-18 Issue:9 Volume:211 Page:1821-1832
ISSN:1540-9538
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Cieslak Agata¹,Le Noir Sandrine¹,Trinquand Amélie¹,Lhermitte Ludovic¹,Franchini Don-Marc²,Villarese Patrick¹,Gon Stéphanie³,Bond Jonathan¹,Simonin Mathieu¹,Vanhille Laurent⁴,Reimann Christian⁵,Verhoeyen Els⁶,Larghero Jerome⁷,Six Emmanuelle⁵,Spicuglia Salvatore⁴,André-Schmutz Isabelle⁵,Langerak Anton⁸,Nadel Bertrand³,Macintyre Elizabeth¹,Payet-Bornet Dominique³,Asnafi Vahid¹

Affiliation:

1. Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, 75015 Paris, France

2. CNRS-Pierre Fabre USR3388, Epigenetic Targeting of Cancer (ETaC), and INSERM UMR1037, Cancer Research Center of Toulouse (CRCT), 31035 Toulouse, France

3. Centre d’Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université UM 2, INSERM UMR 1104, CNRS UMR 7280, 13288 Marseille, France

4. Technological Advances for Genomics and Clinics (TAGC), INSERM U1090, Université de la Méditerranée, 13288 Marseille, France

5. Université Paris-Descartes, Faculté de Médecine René Descartes, IFR94 and INSERM, U768, F-75015 Paris, France

6. CIRI, International center for Infectiology Research, EVIR team, Université de Lyon, INSERM U1111, Lyon, France and Centre Méditerranéen de Médecine Moléculaire (C3M), team “contrôle métabolique des morts cellulaires” Inserm, U1065, 06204 Nice, France

7. Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Unité de Thérapie Cellulaire, Université Paris Diderot, Sorbonne Paris Cité, Inserm CICBT501 et UMR1160, Institut Universitaire d’Hématologie, 75010 Paris, France

8. Department of Immunology, Erasmus MC, University Medical Center, 3016 Rotterdam, Netherlands

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Link

http://rupress.org/jem/article-pdf/211/9/1821/1213910/jem_20132585.pdf

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