Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.
Nat Commun. 2016 Jul 7;7:12091. doi: 10.1038/ncomms12091.
Epigenetic mechanisms such as DNA methylation are essential regulators of the function and information storage capacity of neurons. DNA methylation is highly dynamic in the developing and adult brain, and is actively regulated by neuronal activity and behavioural experiences. However, it is presently unclear how methylation status at individual genes is targeted for modification. Here, we report that extra-coding RNAs (ecRNAs) interact with DNA methyltransferases and regulate neuronal DNA methylation. Expression of ecRNA species is associated with gene promoter hypomethylation, is altered by neuronal activity, and is overrepresented at genes involved in neuronal function. Knockdown of the Fos ecRNA locus results in gene hypermethylation and mRNA silencing, and hippocampal expression of Fos ecRNA is required for long-term fear memory formation in rats. These results suggest that ecRNAs are fundamental regulators of DNA methylation patterns in neuronal systems, and reveal a promising avenue for therapeutic targeting in neuropsychiatric disease states.
表观遗传机制，如 DNA 甲基化，是神经元功能和信息存储能力的重要调节因子。在发育和成年大脑中，DNA 甲基化具有高度动态性，并受到神经元活动和行为经验的积极调节。然而，目前尚不清楚单个基因的甲基化状态如何被靶向修饰。在这里，我们报告说，额外编码的 RNA（ecRNA）与 DNA 甲基转移酶相互作用，并调节神经元 DNA 甲基化。ecRNA 物种的表达与基因启动子低甲基化有关，受神经元活动的影响，并且在参与神经元功能的基因中过度表达。Fos ecRNA 基因座的敲低导致基因超甲基化和 mRNA 沉默，而大鼠海马中 Fos ecRNA 的表达是长期恐惧记忆形成所必需的。这些结果表明，ecRNAs 是神经元系统中 DNA 甲基化模式的基本调节剂，并为神经精神疾病状态的治疗靶向提供了一个有前途的途径。
