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Nucleosome Stability Dramatically Impacts the Targeting of Somatic Hypermutation

机译：核小体的稳定性极大地影响了体细胞超突变的目标。

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Somatic hypermutation (SHM) of immunoglobulin (Ig) genes is initiated by the activation-induced cytidine deaminase (AID). However, the influence of chromatin on SHM remains enigmatic. Our previous cell-free studies indicated that AID cannot access nucleosomal DNA in the absence of transcription. We have now investigated the influence of nucleosome stability on mutability in vivo. We introduced two copies of a high-affinity nucleosome positioning sequence (MP2) into a variable Ig gene region to assess its impact on SHM in vivo. The MP2 sequence significantly reduces the mutation frequency throughout the nucleosome, and especially near its center, despite proportions of AID hot spots similar to those in Ig genes. A weak positioning sequence (M5) was designed based on rules deduced from published whole-genome analyses. Replacement of MP2 with M5 resulted in much higher mutation rates throughout the nucleosome. This indicates that both nucleosome stability and positioning significantly influence the SHM pattern. We postulate that, unlike RNA polymerase, AID has reduced access to stable nucleosomes. This study outlines the limits of nucleosome positioning for SHM of Ig genes and suggests that stable nucleosomes may need to be disassembled for access of AID. Possibly the variable regions of Ig genes have evolved for low nucleosome stability to enhance access to AID, DNA repair factors, and error-prone polymerases and, hence, to maximize variability.
机译：免疫球蛋白（Ig）基因的体细胞超突变（SHM）由激活诱导的胞苷脱氨酶（AID）启动。然而，染色质对SHM的影响仍然是谜。我们先前的无细胞研究表明，在没有转录的情况下，AID无法访问核小体DNA。现在我们已经研究了核小体稳定性对体内变异的影响。我们将高亲和力的核小体定位序列（MP2）的两个副本引入可变的Ig基因区域，以评估其对SHM 体内的影响。尽管AID热点的比例与Ig基因相似，但MP2序列显着降低了整个核小体，尤其是其中心附近的突变频率。根据从公开的全基因组分析得出的规则设计了弱定位序列（M5）。用M5替代MP2导致整个核小体的突变率高得多。这表明核小体的稳定性和位置都显着影响SHM模式。我们推测，与RNA聚合酶不同，AID减少了对稳定核小体的访问。这项研究概述了Ig基因SHM核小体定位的局限性，并建议可能需要拆卸稳定的核小体才能获得AID。 Ig基因的可变区可能已经进化为低核小体稳定性，从而增强了对AID，DNA修复因子和易于出错的聚合酶的获取，从而最大程度地提高了变异性。

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