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.
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.
免疫球蛋白重链（IgH）可变区外显子是在发育中的 B 淋巴细胞中从 V（H）、D 和 J（H）基因片段组装而成的。在 2.7 兆碱基对的小鼠 Igh 基因座内，V(D)J 重组受到调控，以确保特定和多样化的抗体库。在这里，我们在小鼠中报告了一个关键的 Igh V(D)J 重组调控区域，称为基因间控制区 1（IGCR1），它位于 V（H）和 D 簇之间。在功能上，IGCR1 使用 CTCF 环/绝缘子因子结合元件，并相应地介导包含远距离增强子的 Igh 环。IGCR1 通过抑制 D（H）近端 V（H）基因片段的转录和重排以及促进远端 V（H）片段的重排，促进正常 B 细胞发育和平衡抗体库。IGCR1 通过抑制未与 J（H）片段连接的 D 片段与 V（H）的连接，以及分别在胸腺细胞中 V（H）与 DJ（H）的连接，维持有序和谱系特异性的 V（H）（D）J（H）重组。IGCR1 还需要近端 V（H）到 DJ（H）重组的反馈调节和等位基因排斥。我们的研究阐明了一个长期以来寻求的 Igh V(D)J 重组调控区域，并表明一般表达的 CTCF 蛋白具有新的作用。
