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CTCF-binding elements mediate control of V(D)J recombination

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  • Chunguang Guo

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Hye Suk Yoon

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Andrew Franklin

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Suvi Jain

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Anja Ebert

    (Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria)

  • Hwei-Ling Cheng

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Erica Hansen

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Orion Despo

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Claudia Bossen

    (0377, University of California, San Diego, La Jolla, California 92093, USA)

  • Christian Vettermann

    (University of California)

  • Jamie G. Bates

    (University of California)

  • Nicholas Richards

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Darienne Myers

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Harin Patel

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Michael Gallagher

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Mark S. Schlissel

    (University of California)

  • Cornelis Murre

    (0377, University of California, San Diego, La Jolla, California 92093, USA)

  • Meinrad Busslinger

    (Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria)

  • Cosmas C. Giallourakis

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Gastrointestinal Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA)

  • Frederick W. Alt

    (Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA)

Abstract

Immunoglobulin heavy chain (IgH) variable region exons are assembled from VH, D and JH gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the VH and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of DH-proximal VH gene segments and promoting rearrangement of distal VH segments. IGCR1 maintains ordered and lineage-specific VH(D)JH recombination by suppressing VH joining to D segments not joined to JH segments, and VH to DJH joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal VH-to-DJH recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein.

Suggested Citation

  • Chunguang Guo & Hye Suk Yoon & Andrew Franklin & Suvi Jain & Anja Ebert & Hwei-Ling Cheng & Erica Hansen & Orion Despo & Claudia Bossen & Christian Vettermann & Jamie G. Bates & Nicholas Richards & Da, 2011. "CTCF-binding elements mediate control of V(D)J recombination," Nature, Nature, vol. 477(7365), pages 424-430, September.
    • Handle: RePEc:nat:nature:v:477:y:2011:i:7365:d:10.1038_nature10495
    DOI: 10.1038/nature10495
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    Cited by:

    1. Khalid H. Bhat & Saurabh Priyadarshi & Sarah Naiyer & Xinyan Qu & Hammad Farooq & Eden Kleiman & Jeffery Xu & Xue Lei & Jose F. Cantillo & Robert Wuerffel & Nicole Baumgarth & Jie Liang & Ann J. Feene, 2023. "An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Oscar L. Rodriguez & Yana Safonova & Catherine A. Silver & Kaitlyn Shields & William S. Gibson & Justin T. Kos & David Tieri & Hanzhong Ke & Katherine J. L. Jackson & Scott D. Boyd & Melissa L. Smith , 2023. "Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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