The Downstream Transcriptional Enhancer, Ed, Positively Regulates Mouse Igκ Gene Expression and Somatic Hypermutation1
The Downstream Transcriptional Enhancer, Ed, Positively Regulates Mouse Igκ Gene Expression and Somatic Hypermutation1
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DOI：
10.4049/jimmunol.180.10.6725
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发表时间：
2008-05
期刊：
影响因子：
--
通讯作者：
Yougui Xiang;W. Garrard
中科院分区：
文献类型：
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作者：
Yougui Xiang;W. Garrard
小鼠IGκ基因座有三个已知的转录增强子：基质结合区/内含子增强子、3′增强子（E3′）和更下游的增强子（艾德）。已有研究表明，基质结合区/内含子和E3′增强子是该位点最大基因重排所必需的，E3′也是最大表达和体细胞超突变（SHM）所必需的。为了在体内功能上阐明艾德，我们产生了具有靶向的艾德种系缺失的基因敲除小鼠。艾德缺失的纯合子小鼠（艾德-/-）在脾脏中表达IGκ的B细胞的数量适度减少，而表达IGλ的B细胞的数量相应增加。艾德−/−小鼠静息和T细胞依赖性活化脾B细胞中的IGκ mRNA表达也降低，血清中的IGκ链也降低。然而，我们的分析表明，IGκ基因重排是正常的艾德-/-小鼠。此外，我们的研究结果表明，艾德−/−小鼠在派伊尔集合淋巴结的生发中心B细胞中的IGκ基因J-C内含子区域中表现出减少的SHM。我们的结论是，艾德正调控IGκ基因表达和SHM，但不基因重排。
The mouse Igκ locus has three known transcriptional enhancers: the matrix association region/intronic enhancer, the 3′ enhancer (E3′), and the further downstream enhancer (Ed). Previous studies have shown that both matrix association region/intronic and E3′ enhancers are required for maximal gene rearrangement of the locus, and that E3′ is also required for maximal expression and somatic hypermutation (SHM). To functionally elucidate Ed in vivo, we generated knockout mice with a targeted germline deletion of Ed. Ed deleted homozygous mice (Ed−/−) have moderately reduced numbers of Igκ expressing B cells and correspondingly increased numbers of Igλ expressing B cells in spleen. Ed−/− mice also have decreased Igκ mRNA expression in resting and T cell-dependent activated splenic B cells and reduced Igκ chains in sera. However, our analysis indicates that Igκ gene rearrangement is normal in Ed−/− mice. In addition, our results show that Ed−/− mice exhibit reduced SHM in the Igκ gene J-C intronic region in germinal center B cells from Peyer’s patches. We conclude that Ed positively regulates Igκ gene expression and SHM, but not gene rearrangement.