title: CTCF-binding elements mediate control of V(D)J recombination.
abstract: 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.
authors: Howard Hughes Medical Institute, The Children's Hospital, The Immune Disease Institute, Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors: Chunguang
authors: C
authors: Guo
authors: Hye Suk
authors: HS
authors: Yoon
authors: Andrew
authors: A
authors: Franklin
authors: Suvi
authors: S
authors: Jain
authors: Anja
authors: A
authors: Ebert
authors: Hwei-Ling
authors: HL
authors: Cheng
authors: Erica
authors: E
authors: Hansen
authors: Orion
authors: O
authors: Despo
authors: Claudia
authors: C
authors: Bossen
authors: Christian
authors: C
authors: Vettermann
authors: Jamie G
authors: JG
authors: Bates
authors: Nicholas
authors: N
authors: Richards
authors: Darienne
authors: D
authors: Myers
authors: Harin
authors: H
authors: Patel
authors: Michael
authors: M
authors: Gallagher
authors: Mark S
authors: MS
authors: Schlissel
authors: Cornelis
authors: C
authors: Murre
authors: Meinrad
authors: M
authors: Busslinger
authors: Cosmas C
authors: CC
authors: Giallourakis
authors: Frederick W
authors: FW
authors: Alt
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D019070:Cell Lineage / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism; D021901:DNA, Intergenic / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D025461:Feedback, Physiological; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology; D014158:Transcription, Genetic / Q000235:genetics; D050441:VDJ Exons / Q000235:genetics*
chemical_list: D000076246:CCCTC-Binding Factor; C000619698:Ctcf protein, mouse; D021901:DNA, Intergenic; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D012097:Repressor Proteins