Roldán Esther, Fuxa Martin, Chong Winnie, Martinez Dolores, Novatchkova Maria, Busslinger Meinrad, Skok Jane A
Department of Immunology and Molecular Pathology, Division of Infection and Immunity, University College London, London W1T 4JF, UK.
Nat Immunol. 2005 Jan;6(1):31-41. doi: 10.1038/ni1150. Epub 2004 Dec 5.
Allelic exclusion of immunoglobulin genes ensures the expression of a single antibody molecule in B cells through mostly unknown mechanisms. Large-scale contraction of the immunoglobulin heavy-chain (Igh) locus facilitates rearrangements between Igh variable (V(H)) and diversity gene segments in pro-B cells. Here we show that these long-range interactions are mediated by 'looping' of individual Igh subdomains. The Igk locus also underwent contraction by looping in small pre-B and immature B cells, demonstrating that immunoglobulin loci are in a contracted state in rearranging cells. Successful Igh recombination induced the rapid reversal of locus contraction in response to pre-B cell receptor signaling, which physically separated the distal V(H) genes from the proximal Igh domain, thus preventing further rearrangements. In the absence of locus contraction, only the four most proximal V(H) genes escaped allelic exclusion in immature mu-transgenic B lymphocytes. Pre-B cell receptor signaling also led to rapid repositioning of one Igh allele to repressive centromeric domains in response to downregulation of interleukin 7 signaling. These data link both locus 'decontraction' and centromeric recruitment to the establishment of allelic exclusion at the Igh locus.
免疫球蛋白基因的等位基因排斥通过大多未知的机制确保B细胞中单个抗体分子的表达。免疫球蛋白重链（Igh）基因座的大规模收缩促进了前B细胞中Igh可变区（V(H)）和多样性基因片段之间的重排。在这里，我们表明这些长程相互作用是由单个Igh亚结构域的“环化”介导的。Igk基因座在小前B细胞和未成熟B细胞中也通过环化发生收缩，表明免疫球蛋白基因座在重排细胞中处于收缩状态。成功的Igh重组响应前B细胞受体信号传导诱导基因座收缩的快速逆转，这将远端V(H)基因与近端Igh结构域物理分离，从而防止进一步重排。在没有基因座收缩的情况下，只有四个最近端的V(H)基因在未成熟的μ转基因B淋巴细胞中逃脱等位基因排斥。前B细胞受体信号传导还导致一个Igh等位基因响应白细胞介素7信号的下调而快速重新定位到抑制性着丝粒结构域。这些数据将基因座“解收缩”和着丝粒募集都与Igh基因座上等位基因排斥的建立联系起来。
