Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Qld, Australia.
J Neurochem. 2018 Oct;147(2):137-152. doi: 10.1111/jnc.14481. Epub 2018 Aug 1.
Research over the past decade has provided strong support for the importance of various epigenetic mechanisms, including DNA and histone modifications in regulating activity-dependent gene expression in the mammalian central nervous system. More recently, the emerging field of epitranscriptomics revealed an equally important role of post-transcriptional RNA modifications in shaping the transcriptomic landscape of the brain. This review will focus on the methylation of the adenosine base at the N6 position, termed N methyladenosine (m6A), which is the most abundant internal modification that decorates eukaryotic messenger RNAs. Given its prevalence and dynamic regulation in the adult brain, the m6A-epitranscriptome provides an additional layer of regulation on RNA that can be controlled in a context- and stimulus-dependent manner. Conceptually, m6A serves as a molecular switch that regulates various aspects of RNA function, including splicing, stability, localization, or translational control. The versatility of m6A function is typically determined through interaction or disengagement with specific classes of m6A-interacting proteins. Here we review recent advances in the field and provide insights into the roles of m6A in regulating brain function, from development to synaptic plasticity, learning, and memory. We also discuss how aberrant m6A signaling may contribute to neurodevelopmental and neuropsychiatric disorders.
过去十年的研究为各种表观遗传机制的重要性提供了强有力的支持，包括 DNA 和组蛋白修饰在调节哺乳动物中枢神经系统中活性依赖性基因表达中的作用。最近，新兴的转录后 RNA 修饰领域揭示了 RNA 修饰在后转录组学中在塑造大脑转录组图谱方面同样重要的作用。这篇综述将重点介绍腺苷碱基在 N6 位置的甲基化，称为 N6-甲基腺苷（m6A），它是修饰真核信使 RNA 的最丰富的内部修饰。鉴于其在成年大脑中的普遍性和动态调节，m6A-转录组为 RNA 提供了额外的调节层，可以以依赖于上下文和刺激的方式进行控制。从概念上讲，m6A 充当分子开关，调节 RNA 功能的各个方面，包括剪接、稳定性、定位或翻译控制。m6A 功能的多功能性通常通过与特定类别的 m6A 相互作用蛋白的相互作用或脱离来确定。在这里，我们回顾该领域的最新进展，并深入探讨 m6A 在调节从发育到突触可塑性、学习和记忆的大脑功能中的作用。我们还讨论了异常的 m6A 信号传递如何导致神经发育和神经精神疾病。
