{"title":"The role of cytosine methylation in regulating the topology and liquid-liquid phase separation of DNA G-quadruplexes","authors":"Mitsuki Tsuruta, Sumit Shil, Shinya Taniguchi, Keiko Kawauchi, Daisuke Miyoshi","doi":"10.1039/d4sc06959e","DOIUrl":null,"url":null,"abstract":"Aberrant expansion of GGGGCC DNA repeats that form G-quadruplexes (G4) is the main cause of amyotrophic lateral sclerosis (ALS). Expanded GGGGCC repeats induce liquid-liquid phase separation (LLPS) through their interaction with cellular proteins. Furthermore, GGGGCC expansion induces cytosine methylation (mC). Previous studies have shown that even slight chemical modifications of RNAs and proteins can drastically affect their LLPS ability, yet the relationship between LLPS and epigenetic DNA modifications like mC remains unexplored. As a model system, we investigated the effects of mC on LLPS induced by GGGGCC repeat DNAs and show for the first time that mC suppresses LLPS by altering the topology of G4 from being parallel to antiparallel.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"8 1","pages":""},"PeriodicalIF":7.6000,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Science","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4sc06959e","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Aberrant expansion of GGGGCC DNA repeats that form G-quadruplexes (G4) is the main cause of amyotrophic lateral sclerosis (ALS). Expanded GGGGCC repeats induce liquid-liquid phase separation (LLPS) through their interaction with cellular proteins. Furthermore, GGGGCC expansion induces cytosine methylation (mC). Previous studies have shown that even slight chemical modifications of RNAs and proteins can drastically affect their LLPS ability, yet the relationship between LLPS and epigenetic DNA modifications like mC remains unexplored. As a model system, we investigated the effects of mC on LLPS induced by GGGGCC repeat DNAs and show for the first time that mC suppresses LLPS by altering the topology of G4 from being parallel to antiparallel.
GGGGCC DNA 重复序列的异常扩展形成了 G-四重链（G4），这是肌萎缩性脊髓侧索硬化症（ALS）的主要病因。扩展的 GGGGCC 重复序列通过与细胞蛋白质相互作用，诱发液-液相分离（LLPS）。此外，GGGGCC 扩展还会诱导胞嘧啶甲基化（mC）。以往的研究表明，即使对 RNA 和蛋白质进行轻微的化学修饰，也会极大地影响它们的液相分离能力，但液相分离与 mC 等表观遗传 DNA 修饰之间的关系仍未得到探讨。作为一个模型系统，我们研究了 mC 对 GGGGCC 重复 DNA 诱导的 LLPS 的影响，并首次发现 mC 通过改变 G4 的拓扑结构从平行变为反平行来抑制 LLPS。
期刊介绍：
Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.
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