Switch region identity plays an important role in Ig class switch recombination.
Switch region identity plays an important role in Ig class switch recombination.
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DOI：
10.4049/jimmunol.1000507
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Kenter AL
中科院分区：
文献类型：
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作者：
Bhattacharya P;Wuerffel R;Kenter AL
IG类转换重组（CSR）通过生殖系转录启动子和增强子之间的染色体内长距离相互作用来调节，以启动转录并产生可被激活诱导的脱氨酶攻击的染色质。CSR发生在Cμ侧翼的开关（S）区和下游CH区之间，并通过供体Sμ区和下游S区之间的染色体内缺失事件发挥作用。目前尚不清楚S区一级序列在多大程度上影响CSR对特定同种型的差异靶向。我们在这项研究中通过产生突变小鼠来解决这个问题，在突变小鼠中，内源性Sγ3区域被大小匹配的Sγ1序列取代。建立支持稳健的γ3和γ1生殖系转录物表达并刺激IgG 1转换但抑制IgG 3 CSR的B细胞活化条件。我们发现，Sγ1置换等位基因参与μ→γ3 CSR，而完整等位基因被抑制。我们的结论是，S区的身份作出了重大贡献的企业社会责任。我们认为，Sγ1区是选择性靶向CSR诱导后的同种型特异性因子，靶向S区和招募CSR机制。
Ig class switch recombination (CSR) is regulated through long-range intrachromosomal interactions between germline transcript promoters and enhancers to initiate transcription and create chromatin accessible to activation-induced deaminase attack. CSR occurs between switch (S) regions that flank Cμ and downstream CH regions and functions via an intrachromosomal deletional event between the donor Sμ region and a downstream S region. It is unclear to what extent S region primary sequence influences differential targeting of CSR to specific isotypes. We address this issue in this study by generating mutant mice in which the endogenous Sγ3 region was replaced with size-matched Sγ1 sequence. B cell activation conditions are established that support robust γ3 and γ1 germline transcript expression and stimulate IgG1 switching but suppress IgG3 CSR. We found that the Sγ1 replacement allele engages in μ→γ3 CSR, whereas the intact allele is repressed. We conclude that S region identity makes a significant contribution to CSR. We propose that the Sγ1 region is selectively targeted for CSR following the induction of an isotype-specific factor that targets the S region and recruits CSR machinery.