The central dogma postulates that genes are first copied into messenger RNAs, which are then decoded into proteins with the help of transfer RNAs and ribosomal RNAs. It has long been known that there is more to the world of RNA than just these three classes, but the development of high-throughput RNA sequencing has revealed just how active RNAs can be. Much of the genome is transcribed, without these transcripts being translated into proteins. As these non-coding RNAs have been characterized, it is clear that many of them have regulatory roles. It has also been revealed how chemical modifications to all classes of RNAs affect their behavior, such as what they interact with and when, and how long they hang around for before being degraded.
Genome Biology has recently published a special issue on RNA & gene regulation, exploring this new world.
Perhaps some of the best understood regulatory RNAs are the microRNAs, short RNAs that bind to mRNA which mostly causes downregulation by either degrading the mRNA or preventing it from being translated. Although the mechanisms of miRNA regulation have been very well studied, this has mostly been in isolation. In the special issue, Olivia Rissland and coworkers have looked at how miRNAs interact with RNA binding proteins to affect the stability of mRNAs, finding that miRNAs affect the binding of proteins which regulate RNA stability, but without having much affect on polyA tail length as has previously been thought.
Long noncoding RNAs are particularly enigmatic, possibly because the term is a bit of a catch-all term for several different classes of RNA with a variety of functions. Maite Huarte and colleagues have provided a useful Review of the different mechanisms of lncRNA function. The special issue also includes a research paper from the same authors, in which they characterized the role of one particular lncRNA, PINT. They show PINT acts as tumor suppressor by interacting with the Polycomb Repressor Complex 2, hence regulating the expression of genes involved in tumor invasiveness.
Another class of lncRNA arises from antisense transcription, and Wyler et al. have shown that herpes simplex virus causes widespread antisense transcription in cells. This aids infection by preventing apoptosis in the infected cells, allowing the virus to replicate and spread.
As well as non-coding RNAs regulating gene expression, regulation can also be achieved by changes to the mRNA itself. Two reviews in the issue discuss these mechanisms. Chuan He and colleagues explore the many different chemical modifications to RNA and their effects, and Carl Walkley and Jin Billy Li discuss the editing of adenosine to inosine in RNA.
RNA editing is a common theme in the issue, with Walkley and Li and colleagues showing that editing does not seem to be essential in mice, as removing the editing enzymes is broadly tolerated; Porath et al. showing that, although RNA editing may not be required, it is present across a wide variety of animal species; Yi Xing and colleagues finding that there is variation in the extent of editing between individual humans, and identifying sequence variants associated with these changes; and Daniel et al. identifying sequences controlling the efficiency of editing.
Another major source of variation in mRNAs is splicing. Although there are very well-characterized examples of alternative splicing contributing to gene regulation, it is not clear whether all alternative splicing is functional, or whether some if it is just stochastic variation in splicing. Two articles in the special issue explore this. John Rasko and colleagues compare splicing in five different vertebrate species and find that the retention of introns within transcripts is used to increase the complexity of the transcriptome. Saudemont et al. look at splicing in single-celled Paramecium and also in humans and conclude that the majority of splice variants are errors and that the fitness cost of mis-splicing is a major driver of alternative splicing patterns.
The other three articles in the issue published so far all look at how RNA binding proteins can regulate genes. Dorothy Staiger and colleagues perform one of the first iCLIP studies in plants to show that GRP7 binds to mRNAs in order to regulate circadian rhythms in Arabidopsis. Costello et al. investigate how stress in yeast changes the binding of eIF4F to transcripts, thus regulating translation. A study from Fowzan Alkuraya and colleagues in three consanguineous families identifies a mutation in the 3′ UTR of a gene, which affects the binding of a protein known to induce decay of mRNAs, leading to impaired vision.
The special issue was guest-edited by Mihaela Zavolan from the University of Basel and Brenton Graveley from the University of Connecticut.You can read their editorial discussing these exciting times for RNA research here.
Keep an eye out for future articles that are due to be published in the issue in the coming weeks.
Andrew Cosgrove
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