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

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, Darienne Myers, Harin Patel, Michael Gallagher, Mark S. Schlissel, Cornelis Murre, Meinrad Busslinger, Cosmas C. Giallourakis () and Frederick W. Alt ()
Additional contact information
Chunguang Guo: Howard Hughes Medical Institute, The Children’s Hospital, 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
Andrew Franklin: Howard Hughes Medical Institute, The Children’s Hospital, 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
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
Erica Hansen: Howard Hughes Medical Institute, The Children’s Hospital, 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
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
Darienne Myers: Howard Hughes Medical Institute, The Children’s Hospital, 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
Michael Gallagher: Howard Hughes Medical Institute, The Children’s Hospital, 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
Frederick W. Alt: Howard Hughes Medical Institute, The Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA

Nature, 2011, vol. 477, issue 7365, 424-430

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature10495

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