Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin.
Induction of somatic hypermutation is associated with modifications in immunoglobulin variable region chromatin.
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DOI：
10.1016/s1074-7613(03)00261-9
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发表时间：
2003-10
期刊：
影响因子：
32.4
通讯作者：
C. Woo;Alberto Martin;M. Scharff
中科院分区：
文献类型：
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作者：
C. Woo;Alberto Martin;M. Scharff
体细胞超突变（SHM）需要选择性地将突变机制靶向免疫球蛋白重链基因的可变区。共刺激时 BL2 细胞系中 SHM 的诱导与可变区而非恒定区染色质的过度乙酰化相关。由共刺激引起的 V 区限制性组蛋白过度乙酰化的发生与 AID 表达和突变无关。有趣的是，曲古抑菌素 A 存在下的共刺激会导致与恒定区相关的组蛋白过度乙酰化，并将突变延伸至恒定区。在这种情况下，在可变区中也观察到启动子近端突变。 AID 的过度表达会导致类似的突变靶向失调。我们的结果表明，在 BL2 细胞中刺激 SHM 会激活两条独立的途径，导致组蛋白修饰，从而允许诱导的 AID 水平选择性地针对可变区进行突变。
Somatic hypermutation (SHM) requires selective targeting of the mutational machinery to the variable region of the immunoglobulin heavy chain gene. The induction of SHM in the BL2 cell line upon costimulation is associated with hyperacetylation of the chromatin at the variable region but not at the constant region. The V region-restricted histone hyperacetylation resulting from costimulation occurs independent of AID expression and mutation. Interestingly, costimulation in the presence of Trichostatin A causes hyperacetylation of histones associated with the constant region and extends mutations to the constant region. Under this condition, promoter proximal mutations are observed in the variable region as well. The overexpression of AID results in a similar deregulation of mutational targeting. Our results indicate that the stimulation of SHM in BL2 cells activates two independent pathways resulting in histone modifications that permit induced levels of AID to selectively target the variable region for mutation.