Nature：两项研究证实环状RNA影响基因表达

在经典的基因表达模型（中心法则）中，由基因组所编码的基因脚本以RNA分子的形式表达于每一个细胞中，每一个RNA分子由线性的化学"碱基"串联组成。现在是该对基因表达的传统认知进行修订的时候了，科学家们在装满古怪RNA的匣子中看到最新的玩意：天然生成的环状RNA分子影响了基因表达。

同时发表在《自然》（Nature）杂志上的这两项研究，揭示出一些环状RNA充当分子“海绵”，结合并封闭了称作microRNAs的微小基因调控子。此外，研究人员推测环状RNAs还具有许多其他的功能。此外，研究人员推测环状RNAs还具有许多其他的功能。研究人员风趣地表示，这些分子构成了一个“隐秘而未知的RNAs平行宇宙”。

这一重要发现再次提醒人们：RNA并不仅仅是DNA与编码蛋白之间的一个平凡信使。在过去的20年里，研究人员发现了大量的非常规RNA。一些长度意想不到的短，一些则长到令人感到惊讶，而另一些则颠覆常规具有阻止其他RNA链翻译形成蛋白质的功能。

在此之前，环状RNAs一直"飞行于雷达之下"，因为从细胞内分离RNA的传统方法无意中丢弃了这些环状的分子。而实际上，线性RNAs的优势有可能一直是假象。经典的RNA测序方法只能分离具有特征性分子“尾巴“的那些分子。环状RNAs的末端连接在一起，缺乏这些尾巴，因此被普遍忽略掉。环状RNAs比之前预想的更为丰富同时可能比之前所想的更为重要。

然而随着测序技术的进步，使得生物学家们累积了大量的RNA序列数据集，其中一些来自无尾巴的RNA。2012年，斯坦福大学和霍华德休斯医学研究所的科学家们发表在《Plos One》的一项研究首次证实在人体细胞的基因表达程序中，环形RNA分子而非线性RNA分子是一个更普遍的特征。

最新的这两项研究都将焦点放在了由大约1500个核苷酸构成的一个环状大RNA上，它表达于小鼠和人类的大脑中。研究人员发现它包含了70个miR-7的结合位点。MicroRNAs是一些通过结合和阻止mRNA翻译阻断基因表达的短片段RNA。而MiR-7的靶标与癌症和帕金森氏病存在着关联。

第一项研究（Natural RNA circles function as efficient microRNA sponges）发现这一环状RNA的表达阻断了miR-7。它使得miR-7活性受到抑制，miR-7靶基因表达增高，研究人员推测这是因为这一RNA环捕获和失活了miR-7。而另一项研究（Circular RNAs are a large class of animal RNAs with regulatory potency）则证实，在斑马鱼中表达这一环状RNA或敲除miR-7可以改变大脑发育。

研究人员表示，环状RNAs也可能是细胞外microRNA的海绵。一些有可能具有病毒microRNAs的结合位点，从而破坏了免疫应答。他们猜测，环状RNA可能甚至与RNA结合蛋白发挥了互作，原因是它们数量如此的丰富，可能扮演了多种功能角色。

那么RNAs是否还有其他的形状呢？

了解更多：

Natural RNA circles function as efficient microRNA sponges

Nature , 27 February 2013 | doi:10.1038/nature11993

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.

Circular RNAs are a large class of animal RNAs with regulatory potency

Nature, 27 February 2013 | doi:10.1038/nature11928

Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.

Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types

PLoS ONE, February 1, 2012 | doi:10.1371/journal.pone.0030733

Most human pre-mRNAs are spliced into linear molecules that retain the exon order defined by the genomic sequence. By deep sequencing of RNA from a variety of normal and malignant human cells, we found RNA transcripts from many human genes in which the exons were arranged in a non-canonical order. Statistical estimates and biochemical assays provided strong evidence that a substantial fraction of the spliced transcripts from hundreds of genes are circular RNAs. Our results suggest that a non-canonical mode of RNA splicing, resulting in a circular RNA isoform, is a general feature of the gene expression program in human cells.