CTCF-binding elements mediate control of V(D)J recombination
| Autor: | Claudia Bossen, Chunguang Guo, Frederick W. Alt, Andrew Franklin, Darienne Myers, Michael P. Gallagher, Suvi Jain, Cosmas Giallourakis, Orion Despo, Erica Hansen, Jamie G. Bates, Christian Vettermann, Meinrad Busslinger, Anja Ebert, Harin Patel, Cornelis Murre, Mark S. Schlissel, Nicholas Richards, Hwei-Ling Cheng, Hye Suk Yoon |
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| Rok vydání: | 2011 |
| Předmět: |
CCCTC-Binding Factor
Transcription Genetic Gene Rearrangement B-Lymphocyte Heavy Chain Immunoglobulin Variable Region chemical and pharmacologic phenomena Thymus Gland Regulatory Sequences Nucleic Acid Insulator (genetics) Biology Article Mice 03 medical and health sciences 0302 clinical medicine Animals Cell Lineage Enhancer 030304 developmental biology Feedback Physiological Recombination Genetic B-Lymphocytes 0303 health sciences Multidisciplinary V(D)J recombination Gene rearrangement Chromosomes Mammalian Molecular biology Repressor Proteins Allelic exclusion Enhancer Elements Genetic Germ Cells CTCF Mutation Immunoglobulin heavy chain DNA Intergenic VDJ Exons Immunoglobulin Heavy Chains Recombination 030215 immunology |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature10495 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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