中山大学王红胜团队报道了小分子诱导和光激活细胞RNA n1 -甲基腺苷编辑。相关研究成果发表在2024年4月9日出版的《德国应用化学》。

N1甲基腺苷（m1A）修饰是RNA上最普遍的表观遗传学修饰之一。鉴于m1A修饰在RNA加工（如剪接、稳定性和翻译）中的重要作用，开发一种精确可控的m1A编辑工具对于深入研究m1A的生物学功能至关重要。

该文中，研究人员开发了一种脱落酸（ABA）诱导的可逆m1A去甲基化工具（称为AI-dm1A），该工具通过将化学邻近诱导技术与CRISPR/dCas13b系统和ALKBH3相结合来靶向特定的转录物。研究人员成功地使用AI-dm1A选择性地去甲基化MALAT1 A8422处的m1A修饰，并且这种去甲基化过程可以通过去除ABA来逆转。此外，验证了其对各种类型的细胞RNA（包括mRNA、rRNA和lncRNA）的去甲基化功能。

此外，研究人员使用AI-dm1A对ATP5D mRNA进行特异性去甲基化m1A，这促进了ATP5D的表达并增强了肿瘤细胞的糖酵解活性。相反，通过用甲基转移酶TRMT61A取代去甲基酶ALKBH3，研究人员还开发了一种可控的m1A甲基化工具，即AI-m1A。最后，通过4,5-二甲氧基-2-硝基苄基（DMNB）将ABA笼化，以在特定转录物上实现光诱导的m1A甲基化或去甲基化。

总之，该m1A编辑工具使人们能够灵活地研究，特定转录物上的m1A修饰如何影响生物功能和表型。

附：英文原文

Title: Small molecule-inducible and photoactivatable cellular RNA N1-methyladenosine editing

Author: Guoyou Xie, Yunqing Lu, Jiaxin He, Xianyuan Yang, Jiawang Zhou, Cheng Yi, Jian Li, Zigang Li, Gholamreza Asadikaram, Hongxin Niu, Xiaofeng Xiong, Jiexin Li, Hong-Sheng Wang

Issue&Volume: 2024-04-09

Abstract: N1-methyladenosine (m1A) modification is one of the most prevalent epigenetic modifications on RNA. Given the vital role of m1A modification in RNA processing such as splicing, stability and translation, developing a precise and controllable m1A editing tool is pivotal for in-depth investigating the biological functions of m1A. In this study, we developed an abscisic acid (ABA)-inducible and reversible m1A demethylation tool (termed AI-dm1A), which targets specific transcripts by combining the chemical proximity-induction techniques with the CRISPR/dCas13b system and ALKBH3. We successfully employed AI-dm1A to selectively demethylate the m1A modifications at MALAT1 A8422, and this demethylation process could be reversed by removing ABA. Furthermore, we validated its demethylating function on various types of cellular RNAs including mRNA, rRNA and lncRNA. Additionally, we used AI-dm1A to specifically demethylate m1A on ATP5D mRNA, which promoted ATP5D expression and enhanced the glycolysis activity of tumor cells. Conversely, by replacing the demethylase ALKBH3 with methyltransferase TRMT61A, we also developed a controllable m1A methylation tool, namely AI-m1A. Finally, we caged ABA by 4,5-dimethoxy-2-nitrobenzyl (DMNB) to achieve light-inducible m1A methylation or demethylation on specific transcripts. Collectively, our m1A editing tool enables us to flexibly study how m1A modifications on specific transcript influence biological functions and phenotypes.

DOI: 10.1002/anie.202320029

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202320029