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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Complex regulation of somatic hypermutation by cis-acting sequences in the endogenous IgH gene in hybridoma cells
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Complex regulation of somatic hypermutation by cis-acting sequences in the endogenous IgH gene in hybridoma cells

机译：杂交瘤细胞内源IgH基因中顺式作用序列对体细胞高突变的复杂调控

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摘要

To create high-affinity antibodies, B cells target a high rate of somatic hypermutation (SHM) to the Ig variable-region genes that encode the antigen-binding site. This mutational process requires transcription and is triggered by activation-induced cytidine deaminase (AID), which converts deoxycytidine to deoxyuridine. Mistargeting of AID to non-Ig genes is thought to result in the malignant transformation of B cells, but the mechanism responsible for targeting SHIM to certain DNA regions and not to others is largely unknown. Cis-acting elements have been proposed to play a role in directing the hypermutation machinery, but the motifs required for targeting SHM have been difficult to identify because many of the candidate elements, such as promoters or enhancers, are also required for transcription of Ig genes. Here we describe a system in cultured hybridoma cells in which transcription of the endogenous heavy-chain Ig gene continues in the absence of the core intronic enhancer (E mu) and its flanking matrix attachment regions (MARs). When AID is expressed in these cells, SHM occurred at the WT frequency even when Eft and the MARs were absent together. Interestingly, SHM occurred at less than the WT frequency when E mu or the MARs were individually absent. Our results suggest that these intronic regulatory elements can exert a complex influence on SHM that is separable from their role in regulating transcription.
机译：为了产生高亲和力的抗体，B细胞将高比率的体细胞超突变（SHM）靶向编码抗原结合位点的Ig可变区基因。此突变过程需要转录，并由激活诱导的胞苷脱氨酶（AID）触发，该酶将脱氧胞苷转化为脱氧尿苷。人们认为，将AID误定位到非Ig基因会导致B细胞发生恶性转化，但是将SHIM靶向某些DNA区域而不是其他DNA的机制尚不清楚。已经提出了顺式作用元件在指导超突变机制中起作用，但是靶向SHM所需的基序很难鉴定，因为Ig基因的转录也需要许多候选元件，例如启动子或增强子。 。在这里，我们描述了一个在培养的杂交瘤细胞中的系统，其中内源重链Ig基因的转录在没有核心内含子增强子（E mu）及其侧翼基质附着区（MARs）的情况下继续进行。当在这些单元格中表达AID时，即使Eft和MAR一起不存在，SHM也会以WT频率发生。有趣的是，当单独不存在E mu或MAR时，SHM发生的频率小于WT频率。我们的结果表明，这些内含子调节元件可以对SHM产生复杂的影响，这与其在调节转录中的作用是可分离的。

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