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

Agata Cieslak; Sandrine L. le Noir; Amélie Trinquand; Ludovic Lhermitte; Don Marc Franchini; Patrick Villarese; Stéphanie Gon; Jonathan Bond; Mathieu Simonin; Laurent Vanhile; Christian Reimann; Els Verhoeyen; Jerome Larghero; Emmanuelle Six; Salvatore Spicuglia; Isabelle André-Schmutz; Anton Langerak; Bertrand Nadel; Elizabeth Macintyre; Dominique Payet-Bornet; Vahid Asnafi

doi:10.1084/jem.20132585

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

Agata Cieslak, Sandrine L. le Noir, Amélie Trinquand, Ludovic Lhermitte, Don Marc Franchini, Patrick Villarese, Stéphanie Gon, Jonathan Bond, Mathieu Simonin, Laurent Vanhile, Christian Reimann, Els Verhoeyen, Jerome Larghero, Emmanuelle Six, Salvatore Spicuglia, Isabelle André-Schmutz, Anton Langerak, Bertrand Nadel, Elizabeth Macintyre, Dominique Payet-Bornet^*Vahid Asnafi^*

^*Corresponding author for this work

Immunology

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	1821-1832
Number of pages	12
Journal	Journal of Experimental Medicine
Volume	211
Issue number	9
DOIs	https://doi.org/10.1084/jem.20132585
Publication status	Published - 2014

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RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangementFinal published version, 2.56 MBLicence: CC BY-NC-SA

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Cieslak, A., le Noir, S. L., Trinquand, A., Lhermitte, L., Franchini, D. M., Villarese, P., Gon, S., Bond, J., Simonin, M., Vanhile, L., Reimann, C., Verhoeyen, E., Larghero, J., Six, E., Spicuglia, S., André-Schmutz, I., Langerak, A., Nadel, B., Macintyre, E., ... Asnafi, V. (2014). RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement. Journal of Experimental Medicine, 211(9), 1821-1832. https://doi.org/10.1084/jem.20132585

@article{e9b6f484843542d5875baff5172e1550,

title = "RUNX1-dependent RAG1 deposition instigates human TCR-δ 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-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.",

author = "Agata Cieslak and {le Noir}, {Sandrine L.} and Am{\'e}lie Trinquand and Ludovic Lhermitte and Franchini, {Don Marc} and Patrick Villarese and St{\'e}phanie Gon and Jonathan Bond and Mathieu Simonin and Laurent Vanhile and Christian Reimann and Els Verhoeyen and Jerome Larghero and Emmanuelle Six and Salvatore Spicuglia and Isabelle Andr{\'e}-Schmutz and Anton Langerak and Bertrand Nadel and Elizabeth Macintyre and Dominique Payet-Bornet and Vahid Asnafi",

year = "2014",

doi = "10.1084/jem.20132585",

language = "English",

volume = "211",

pages = "1821--1832",

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Cieslak, A, le Noir, SL, Trinquand, A, Lhermitte, L, Franchini, DM, Villarese, P, Gon, S, Bond, J, Simonin, M, Vanhile, L, Reimann, C, Verhoeyen, E, Larghero, J, Six, E, Spicuglia, S, André-Schmutz, I, Langerak, A, Nadel, B, Macintyre, E, Payet-Bornet, D & Asnafi, V 2014, 'RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement', Journal of Experimental Medicine, vol. 211, no. 9, pp. 1821-1832. https://doi.org/10.1084/jem.20132585

TY - JOUR

T1 - RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement

AU - Cieslak, Agata

AU - le Noir, Sandrine L.

AU - Trinquand, Amélie

AU - Lhermitte, Ludovic

AU - Franchini, Don Marc

AU - Villarese, Patrick

AU - Gon, Stéphanie

AU - Bond, Jonathan

AU - Simonin, Mathieu

AU - Vanhile, Laurent

AU - Reimann, Christian

AU - Verhoeyen, Els

AU - Larghero, Jerome

AU - Six, Emmanuelle

AU - Spicuglia, Salvatore

AU - André-Schmutz, Isabelle

AU - Langerak, Anton

AU - Nadel, Bertrand

AU - Macintyre, Elizabeth

AU - Payet-Bornet, Dominique

AU - Asnafi, Vahid

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84906537020&partnerID=8YFLogxK

U2 - 10.1084/jem.20132585

DO - 10.1084/jem.20132585

M3 - Article

C2 - 25135298

AN - SCOPUS:84906537020

SN - 0022-1007

VL - 211

SP - 1821

EP - 1832

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 9

ER -

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

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