Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Université de Limoges, Limoges, France.
J Immunol. 2010 Apr 1;184(7):3710-7. doi: 10.4049/jimmunol.0901978. Epub 2010 Feb 22.
In the mouse, the regulatory region located at the 3' end of the IgH locus includes four transcriptional enhancers: HS3a, HS1-2, HS3b, and HS4; the first three lie in a quasi-palindromic structure. Although the upstream elements HS3a and HS1-2 proved dispensable for Ig expression and class switch recombination (CSR), the joint deletion of HS3b and HS4 led to a consistent decrease in IgH expression in resting B cells and to a major CSR defect. Within this pair of distal enhancers, it was questionable whether HS3b and HS4 could be considered individually as elements critical for IgH expression and/or CSR. Studies in HS4-deficient mice recently revealed the role of HS4 as restricted to Igmicro-chain expression from the pre-B to the mature B cell stage and left HS3b as the last candidate for CSR regulation. Our present study finally invalidates the hypothesis that CSR could mostly rely on HS3b itself. B cells from HS3b-deficient animals undergo normal proliferation, germline transcription, and CSR upon in vitro stimulation with LPS; in vivo Ag-specific responses are not affected. In conclusion, our study highlights a major effect of the global ambiance of the IgH locus; enhancers demonstrated as being strongly synergistic in transgenes turn out to be redundant in their endogenous context.
在小鼠中，位于 IgH 基因座 3' 端的调控区包括四个转录增强子：HS3a、HS1-2、HS3b 和 HS4；前三个位于准回文结构中。虽然上游元件 HS3a 和 HS1-2 被证明对 Ig 表达和类别转换重组（CSR）是可有可无的，但 HS3b 和 HS4 的联合缺失导致静止 B 细胞中 IgH 表达的持续下降，并导致 CSR 主要缺陷。在这对远端增强子中，HS3b 和 HS4 是否可以被单独视为 IgH 表达和/或 CSR 的关键元件是有争议的。最近在 HS4 缺陷型小鼠中的研究揭示了 HS4 的作用仅限于 Igmicro 链从 pre-B 细胞到成熟 B 细胞阶段的表达，而 HS3b 则成为 CSR 调控的最后一个候选者。我们目前的研究最终否定了 CSR 主要依赖于 HS3b 本身的假设。HS3b 缺陷型动物的 B 细胞在体外用 LPS 刺激时会正常增殖、进行 germline 转录和 CSR；体内 Ag 特异性反应不受影响。总之，我们的研究强调了 IgH 基因座整体环境的主要影响；在转基因中表现出强烈协同作用的增强子在其内源性背景中是冗余的。
