Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline
Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline
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DOI：
10.1093/hmg/ddn019
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Wilson, John H.
中科院分区：
文献类型：
--
作者：
Dion, Vincent;Lin, Yunfu;Wilson, John H.
扩大的 CAG 重复束是至少十几种神经退行性疾病的原因。在人类中，长 CAG 重复序列在从亲本传播到后代的过程中往往会扩大，导致疾病发病年龄更早，后代症状更严重。在这里，我们发现维持性 DNA 甲基转移酶 Dnmt1 保留了 CpG 甲基化模式，在人类细胞以及雄性和雌性小鼠种系中的 CAG 重复不稳定性中发挥着关键作用。人类细胞中 Dnmt1 的 SiRNA 敲低会破坏 CAG 三联体重复序列的稳定性，而小鼠中 Dnmt1 缺陷则促进小鼠脊髓小脑共济失调 1 型 (Sca1) 基因座处 CAG 重复序列的代际扩增。重要的是，Dnmt1(+/-) SCA1 小鼠与 Dnmt1(+/+) SCA1 小鼠不同，它密切地再现了在人类 SCA1 患者中观察到的代际不稳定模式。此外，我们在 Dnmt1 缺陷小鼠的 CpG 岛内邻近扩展重复序列的位点发现了异常 DNA 和组蛋白甲基化。这些研究表明局部染色质结构可能在三联体重复不稳定中发挥作用。这些结果与种系发育过程中导致小鼠和人类 CAG 重复代际不稳定性的正常表观遗传变化一致。
Expanded CAG repeat tracts are the cause of at least a dozen neurodegenerative disorders. In humans, long CAG repeats tend to expand during transmissions from parent to offspring, leading to an earlier age of disease onset and more severe symptoms in subsequent generations. Here, we show that the maintenance DNA methyltransferase Dnmt1, which preserves the patterns of CpG methylation, plays a key role in CAG repeat instability in human cells and in the male and female mouse germlines. SiRNA knockdown of Dnmt1 in human cells destabilized CAG triplet repeats, and Dnmt1 deficiency in mice promoted intergenerational expansion of CAG repeats at the murine spinocerebellar ataxia type 1 (Sca1) locus. Importantly, Dnmt1(+/-) SCA1 mice, unlike their Dnmt1(+/+) SCA1 counterparts, closely reproduced the intergenerational instability patterns observed in human SCA1 patients. In addition, we found aberrant DNA and histone methylation at sites within the CpG island that abuts the expanded repeat tract in Dnmt1-deficient mice. These studies suggest that local chromatin structure may play a role in triplet repeat instability. These results are consistent with normal epigenetic changes during germline development contributing to intergenerational instability of CAG repeats in mice and in humans.