CSIRO Food and Nutrition Flagship, Sydney, New South Wales, Australia.
1] CSIRO Food and Nutrition Flagship, Sydney, New South Wales, Australia [2] Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Mol Ther Nucleic Acids. 2014 Oct 14;3(10):e203. doi: 10.1038/mtna.2014.54.
Argonautes are highly conserved proteins found in almost all eukaryotes and some bacteria and archaea. In humans, there are eight argonaute proteins evenly distributed across two clades, the Ago clade (AGO1-4) and the Piwi clade (PIWIL1-4). The function of Ago proteins is best characterized by their role in RNA interference (RNAi) and cytoplasmic post-transcriptional gene silencing (PTGS) - which involves the loading of siRNA or miRNA into argonaute to direct silencing of genes at the posttranscriptional or translational level. However, nuclear-localized, as opposed to cytoplasmic, argonaute-small RNA complexes may also orchestrate the mechanistically very different process of transcriptional gene silencing, which results in prevention of transcription from a gene locus by the formation of silent chromatin domains. More recently, the role of argonaute in other aspects of epigenetic regulation of chromatin, alternative splicing and DNA repair is emerging. This review focuses on the activity of nuclear-localized short RNA-argonaute complexes in a mammalian setting and discusses recent in vivo studies employing nuclear-directed sRNA for therapeutic interventions. These studies heed the potential development of RNA-based drugs which induce epigenetic changes in the cell.
Argonautes 是一种高度保守的蛋白质，几乎存在于所有真核生物和一些细菌及古菌中。在人类中，有 8 种 Argonaute 蛋白均匀分布在两个分支中，AGO 分支（AGO1-4）和 Piwi 分支（PIWIL1-4）。Argonaute 蛋白的功能主要通过其在 RNA 干扰（RNAi）和细胞质转录后基因沉默（PTGS）中的作用来表征——这涉及到将 siRNA 或 miRNA 加载到 Argonaute 中，以指导基因在转录后或翻译水平上的沉默。然而，核定位的 Argonaute-小 RNA 复合物，而不是细胞质定位的复合物，也可能协调转录基因沉默这一机制上非常不同的过程，从而通过形成沉默染色质域来阻止基因座的转录。最近，Argonaute 在染色质表观遗传调控、可变剪接和 DNA 修复等方面的作用也逐渐显现出来。这篇综述重点介绍了核定位短 RNA-Argonaute 复合物在哺乳动物环境中的活性，并讨论了最近利用核定向 sRNA 进行治疗干预的体内研究。这些研究关注了基于 RNA 的药物的潜在发展，这种药物可以在细胞中诱导表观遗传变化。
