Elsevier

Biochimie

Volume 93, Issue 11, November 2011, Pages 1905-1915
Biochimie

Review
Small RNAs derived from longer non-coding RNAs

https://doi.org/10.1016/j.biochi.2011.07.032Get rights and content

Abstract

Posttranscriptional gene regulation by small RNAs and its crucial impact on development, apoptosis, stem cell self-renewal and differentiation gained tremendous scientific attention since the discovery of RNA interference (RNAi) and microRNAs (miRNAs). However, in the last few years, many more examples for regulatory small RNAs were discovered, some of them even with miRNA-like functions. Even though these small RNA molecules were previously thought to be mere artifacts accumulating during the preparation of RNA libraries, advances in sequencing technology revealed that small RNAs derive from hairpin-fold RNA structures, for example. Mirtrons, short hairpin RNAs or small RNAs that are processed from longer non-coding RNAs such as tRNAs or snoRNAs have been found recently and some of them might be involved in the regulation of gene expression in different organisms. Furthermore, small RNAs originating from transposable elements, heterochromatic regions or convergent transcription units forming endogenous short interfering RNAs (endo-siRNAs) are the somatic equivalents of the germline-specific Piwi-interacting RNAs (piRNAs) in mediating transposon silencing.

This review will focus on several recent findings that have added new aspects to small RNA-guided gene silencing.

Highlights

► miRNAs, piRNAs and siRNAs are known as key regulators for accurate cell function. ► Novel classes of small RNAs derived from long non-coding RNAs were discovered recently. ► Small RNAs therefore greatly enlarge the cell’s toolbox for gene regulation.

Introduction

When in 1998 RNA interference (RNAi) was discovered by A. Fire and C. Mello [1], this phenomenon was considered to be a revolutionary tool to study gene function. However, in the last decade endogenous small non-coding RNAs were identified and it became evident that small RNAs form a novel layer of gene regulation with fundamental roles for accurate cell function. MicroRNAs (miRNA) (endogenous) short interfering RNAs (siRNAs, endo-siRNAs) and piwi interacting RNAs (piRNAs) are now known as key regulators of processes as diverse as development, apoptosis, stem cell self-renewal, differentiation and maintenance of cell integrity. Recently, more and more small RNA species deriving from other, longer non-coding RNAs were discovered. Considering the fact that although eukaryotic genomes transcribe up to 90–95% of the genomic DNA, less than 2–3% encode for proteins [2], [3], it is evident that non-coding RNAs might have a more important role than previously thought. Indeed, deep sequencing technologies followed by extensive bioinformatics-based characterization of genomic locations and RNA secondary structure predictions revealed the existence of a vast amount of small RNAs some of them even having miRNA-like functions in posttranscriptional gene regulation. These exciting findings highlight the importance of small RNAs in gene regulation. This review will summarize the most recent findings in the field of small RNAs deriving from longer non-coding RNA species.

Section snippets

Non-coding RNAs (ncRNAs)

Traditionally, ncRNAs are divided into long ncRNAs (>200–300 nucleotides (nt)) and shorter (<200–300 nt) species of ncRNAs (Table 1) [4], [5].

Long ncRNAs, ranging from approximately 200 to several thousands of nt in size, are transcribed by RNA polymerase II, 5′ capped, spliced and polyadenylated [6]. Most examples described to date (reviewed in [6], [7], [8], [9]) are involved in genomic imprinting (such as for example Kcnq1ot1), an epigenetic phenomenon by which a subset of genes is

Small RNAs and the regulation of gene expression

Small RNA-guided posttranscriptional regulation of gene expression is mainly covered by small RNAs (sRNAs) of 18–35 nt in size. In many organisms, the best studied representatives are miRNAs, siRNAs and piRNAs. More recently, ongoing research discovered new classes of sRNA such as endogenous siRNAs (endo-siRNAs), mirtrons, miRNA-like sRNAs derived from longer ncRNAs (tRNAs or snoRNAs), short hairpin RNAs (shRNAs), small vault RNAs (svRNAs), microRNA-offset RNAs (moRs) and QDE2-interacting small

Perspective

Considering the complex relationships between small RNAs, the RNA silencing machinery and their impact on the stable maintenance of the cell, it is evident that identification and characterization of all small RNAs involved in regulatory processes and the discovery of so far unknown modes of regulation by small RNAs is of high biological impact. Many laboratories demonstrate the existence of small RNAs with siRNA-like or miRNA-like functions, however it is important to note that so far only a

Acknowledgements

Our work is supported by a grant from the European research council (ERC, ‘sRNAs’) and the Bayerisches Staatsministerium für Wissenschaft, Forschung und Kunst (BayGene to G.M.). S.R. is supported by an EMBO long term fellowship.

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