Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
J Immunol. 2011 Nov 1;187(9):4733-43. doi: 10.4049/jimmunol.1101808. Epub 2011 Sep 26.
Class-switch recombination of Ab isotype is mediated by a recombinational DNA deletion event and must be robustly upregulated during Ag-driven differentiation of B cells. The enhancer region 3' of the Cα gene is important for the upregulation of switch recombination. Using a transgene of the entire H chain C region locus, we demonstrate in this study that it is the four 3' enhancer elements themselves (a total of 4.7 kb) that are responsible for the upregulation rather than the 24 kb of DNA in between them. Neither allelic exclusion nor transgenic μ expression is reduced by deletion of the four 3' enhancers. We also test deletions of two or three of the 3' enhancers and show that deletion of more 3' enhancers results in a progressive reduction in both switch recombination and germline transcription of all H chain genes. Nevertheless, we find evidence for special roles for some 3' enhancers; different H chain genes are affected by different 3' enhancer deletions. Thus, we find that the dramatic induction of class-switch recombination during Ag-driven differentiation is the result of an interaction among four separated regulatory elements.
Ab 同种型的类别转换重组是由重组 DNA 缺失事件介导的，并且必须在 B 细胞的 Ag 驱动分化过程中被强烈地上调。Cα 基因 3'端的增强子区域对于开关重组的上调很重要。在本研究中，我们使用整个 H 链 C 区基因座的转基因，证明正是这四个 3'增强子本身（总共 4.7kb）负责上调，而不是它们之间的 24kb DNA。四个 3'增强子的缺失既不会降低等位基因排斥，也不会降低转基因 μ 的表达。我们还测试了三个 3'增强子中的两个或三个的缺失，并表明删除更多的 3'增强子会导致所有 H 链基因的开关重组和种系转录逐渐减少。然而，我们发现一些 3'增强子具有特殊作用的证据；不同的 H 链基因受到不同的 3'增强子缺失的影响。因此，我们发现，在 Ag 驱动的分化过程中，类别转换重组的剧烈诱导是四个分离的调节元件之间相互作用的结果。
