The effects of molecular crowding and CpG hypermethylation on DNA G-quadruplexes formed by the C9orf72 nucleotide repeat expansion.
The effects of molecular crowding and CpG hypermethylation on DNA G-quadruplexes formed by the C9orf72 nucleotide repeat expansion.
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DOI：
10.1038/s41598-021-02041-4
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发表时间：
2021-12-01
影响因子：
4.6
通讯作者：
Haeusler AR
中科院分区：
文献类型：
--
作者：
Ozcan KA;Ghaffari LT;Haeusler AR
位于C9 orf 72（C9）经典非编码区的核苷酸重复序列扩增（NRE）（G4 C2）n是与ALS/FTD相关的最常见遗传突变。越来越多的证据表明，由C9-NRE形成的核酸结构既可能导致ALS/FTD，也可能作为治疗靶点，但在生理学和疾病相关条件下对这些核酸结构的表征有限。在这里，我们表明，在体外C9-NRE DNA可以形成平行和反平行的DNA G-四链体（GQ）的拓扑结构，这些DNA GQ的结构偏好可以依赖于分子拥挤条件。此外，在一些患者的C9-NRE基因座中观察到的5-甲基胞嘧啶DNA超甲基化对GQ拓扑偏好的影响最小。最后，甲基化和非甲基化GQ结构的分子动力学模拟支持体外数据，表明由C9-NRE DNA形成的DNA GQ结构是稳定的，结构波动限于含胞嘧啶的环区域。这些发现为C9-NRE在甲基化和非甲基化状态下形成的DNA GQ的结构多态性偏好和稳定性提供了新的见解，并揭示了指导上游治疗方法发展的重要特征，以潜在地减轻C9-NRE相关疾病。
A nucleotide repeat expansion (NRE), (G4C2)n, located in a classically noncoding region of C9orf72 (C9), is the most common genetic mutation associated with ALS/FTD. There is increasing evidence that nucleic acid structures formed by the C9-NRE may both contribute to ALS/FTD, and serve as therapeutic targets, but there is limited characterization of these nucleic acid structures under physiologically and disease relevant conditions. Here we show in vitro that the C9-NRE DNA can form both parallel and antiparallel DNA G-quadruplex (GQ) topological structures and that the structural preference of these DNA GQs can be dependent on the molecular crowding conditions. Additionally, 5-methylcytosine DNA hypermethylation, which is observed in the C9-NRE locus in some patients, has minimal effects on GQ topological preferences. Finally, molecular dynamic simulations of methylated and nonmethylated GQ structures support in vitro data showing that DNA GQ structures formed by the C9-NRE DNA are stable, with structural fluctuations limited to the cytosine-containing loop regions. These findings provide new insight into the structural polymorphic preferences and stability of DNA GQs formed by the C9-NRE in both the methylated and nonmethylated states, as well as reveal important features to guide the development of upstream therapeutic approaches to potentially attenuate C9-NRE-linked diseases.
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