科學(xué)家們在裝滿古怪RNA的匣子中看到最新的玩意：天然生成的環(huán)狀RNA分子影響了基因表達(dá),。

在最新一期（2月27日）《自然》（Nature）雜志上,，兩篇重要的研究論文揭示出一些環(huán)狀RNA充當(dāng)分子“海綿”,，結(jié)合并封閉了稱作microRNAs的微小基因調(diào)控子。此外,，研究人員推測環(huán)狀RNAs還具有許多其他的功能。其中一篇Nature文章的主要作者,、德國Max Delbrück分子醫(yī)學(xué)中心系統(tǒng)生物學(xué)家Nikolaus Rajewsky說,，這些分子構(gòu)成了一個“隱秘的未知RNAs平行宇宙”。

這一發(fā)現(xiàn)再次提醒人們：RNA并不僅僅是DNA與編碼蛋白之間的一個平凡信使,。在過去的20年里,，研究人員發(fā)現(xiàn)了大量的非常規(guī)RNA。一些長度意想不到的短,，一些則長到令人感到驚訝,，而另一些則顛覆常規(guī)具有阻止其他RNA鏈翻譯形成蛋白質(zhì)的功能。幾乎所有的RNA都是線性的,，為數(shù)不多的關(guān)于植物和動物中的環(huán)狀RNAs的記述,，也被當(dāng)做遺傳意外或?qū)嶒炄藶橐蛩囟獾胶鲆暋?/p>

實際，線性RNAs的優(yōu)勢有可能一直是假象,。經(jīng)典的RNA測序方法只能分離具有特征性分子“尾巴“的那些分子,。環(huán)狀RNAs的末端連接在一起，缺乏這些尾巴,，因此被普遍忽略掉,。

然而隨著測序技術(shù)的進(jìn)步,，使得生物學(xué)家們累積了大量的RNA序列數(shù)據(jù)集，其中一些來自無尾巴的RNA,。去年,，斯坦福大學(xué)醫(yī)學(xué)院的分子生物學(xué)家Julia Salzman和同事們送出了來自這一環(huán)狀宇宙的第一份信函。他們報道稱在尋找用傳統(tǒng)方法可能忽視的RNA過程中,，發(fā)現(xiàn)了過量的環(huán)狀人類RNAs,。當(dāng)Rajewsky和同事們挖掘環(huán)狀RNA分子的數(shù)據(jù)庫時，他們在線蟲,、小鼠和人類中發(fā)現(xiàn)了成千上萬的環(huán)狀RNAs,。

Sontheimer說：“這是另一個極好的例子，表明一種重要的RNA在雷達(dá)下飛行,。”

丹麥奧胡斯大學(xué)的Thomas Hansen和Jorgen Kjems領(lǐng)導(dǎo)的另一個獨立研究小組完成了第二篇Nature論文研究,。這兩篇論文都將焦點放在了由大約1500個核苷酸構(gòu)成的一個環(huán)狀大RNA上，它表達(dá)于小鼠和人類的大腦中,。研究人員發(fā)現(xiàn)它包含了70個miR-7的結(jié)合位點,。MicroRNAs是一些通過結(jié)合和阻止mRNA翻譯阻斷基因表達(dá)的短片段RNA。一直以來人們知道,，MiR-7的靶標(biāo)與癌癥和帕金森氏病存在著關(guān)聯(lián),。

Hansen研究小組發(fā)現(xiàn)這一環(huán)狀RNA的表達(dá)阻斷了miR-7。它使得miR-7活性受到抑制,，miR-7靶基因表達(dá)增高,，研究人員推測這是因為這一RNA環(huán)捕獲和失活了miR-7。Rajewsky研究小組證實,，在斑馬魚中表達(dá)這一環(huán)狀RNA或敲除miR-7可以改變大腦發(fā)育,。

Rajewsky說，環(huán)狀RNAs也可能是細(xì)胞外microRNA的海綿,。一些有可能具有病毒microRNAs的結(jié)合位點,，從而破壞了免疫應(yīng)答。Rajewsky猜測,，環(huán)狀RNA可能甚至與RNA結(jié)合蛋白發(fā)揮了互作,。Salzman表示同意：“它們數(shù)量如此的豐富，可能扮演了多種功能角色,。”

那么RNAs是否還有其他的形狀?“我不認(rèn)為我們可能錯過了其他的形式,。但你知道總會有人找到它，”劍橋麻省理工學(xué)院分子生物學(xué)家Phillip Sharp笑著說,。(生物谷Bioon.com)

doi:10.1038/nature11928
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Circular RNAs are a large class of animal RNAs with regulatory potency

Sebastian Memczak, Marvin Jens,Antigoni Elefsinioti, Francesca Torti,Janna Krueger, Agnieszka Rybak, Luisa Maier, Sebastian D- Mackowiak, Lea H. Gregersen, Mathias Munschauer, Alexander Loewer, Ulrike Ziebold, Markus Landthaler, Christine Kocks, Ferdinand le Noble & Nikolaus Rajewsky.

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.

doi:10.1038/nature11993
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Natural RNA circles function as efficient microRNA sponges

Thomas B-Hansen, Trine I-Jensen, Bettina H-Clausen, Jesper B-Bramsen, Bente Finsen, Christian K-Damgaard & Jorgen Kjems.

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs1. 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 plants2, 3, 4, 5, 6, 7. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain8. 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)9, 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.