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

Nature. 2011 Sep 11;477(7365):424-30. doi: 10.1038/nature10495.


Immunoglobulin heavy chain (IgH) variable region exons are assembled from V(H), D and J(H) 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 V(H) 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 D(H)-proximal V(H) gene segments and promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination by suppressing V(H) joining to D segments not joined to J(H) segments, and V(H) to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V(H)-to-DJ(H) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism
  • CCCTC-Binding Factor
  • Cell Lineage / genetics
  • Chromosomes, Mammalian / genetics
  • Chromosomes, Mammalian / metabolism
  • DNA, Intergenic / genetics*
  • Enhancer Elements, Genetic / genetics
  • Feedback, Physiological
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain / genetics*
  • Germ Cells / metabolism
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Variable Region / genetics
  • Mice
  • Mutation / genetics
  • Recombination, Genetic / genetics*
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Repressor Proteins / metabolism*
  • Thymus Gland / cytology
  • Transcription, Genetic / genetics
  • VDJ Exons / genetics*


  • CCCTC-Binding Factor
  • Ctcf protein, mouse
  • DNA, Intergenic
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Repressor Proteins