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RNA Biology

Volume 14, 2017 - Issue 12
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Point of View

A-to-I RNA editing – thinking beyond the single nucleotide

Nabeel S. Ganem Faculty of Biology, Technion- Israel Institute of Technology, Technion City, Haifa, IsraelORCID Iconhttp://orcid.org/0000-0002-8326-660X
ORCID Icon &
Ayelet T. Lamm Faculty of Biology, Technion- Israel Institute of Technology, Technion City, Haifa, IsraelCorrespondenceayeletla@technion.ac.il
ORCID Iconhttp://orcid.org/0000-0002-5973-5218
ORCID Icon
Pages 1690-1694
Received 30 Jun 2017
Accepted 02 Aug 2017
Accepted author version posted online: 18 Aug 2017
Published online: 11 Oct 2017

Point of View

A-to-I RNA editing – thinking beyond the single nucleotide

ABSTRACT

ABSTRACT

Adenosine-to-inosine RNA editing is a conserved process, which is performed by ADAR enzymes. By changing nucleotides in coding regions of genes and altering codons, ADARs expand the cell's protein repertoire. This function of the ADAR enzymes is essential for human brain development. However, most of the known editing sites are in non-coding repetitive regions in the transcriptome and the purpose of editing in these regions is unclear. Recent studies, which have shown that editing levels of transcripts vary between tissues and developmental stages in many organisms, suggest that the targeted RNA and ADAR editing are both regulated. We discuss the implications of these findings, and the possible role of RNA editing in innate immunity.

Introduction

In recent years, many novel posttranscriptional modifications were found in numerous organisms,1,2 including dozens in human, increasing our knowledge of the variation and repertoire of RNA in the cells. However, much is unknown about these modifications. We still do not know the particular function of each modification, the specific RNA molecules being modified, and in which tissues and developmental stages these modifications occur. One of the most studied RNA modifications, which was discovered almost 30 y ago, is A-to-I RNA editing.3,4 A-to-I RNA editing is the deamination of adenosine (A) to inosine (I) within a largely double stranded RNA structure. The deamination is performed by enzymes belonging to the adenosine deaminase acting on RNA (ADAR) family that are found across metazoans.5,6 There are three ADAR genes in the human genome; ADAR1 and ADAR2 are expressed in most tissues, are enzymatically active, and are essential, while ADAR3 is exclusively expressed in the brain and its enzymatic activity is questionable (reviewed in7,8). ADAR proteins are composed of two main motifs, a highly conserved C-terminal catalytic deaminase domain, and a variable number of double-stranded RNA binding domains (dsRBD).9 For many years, it was thought that the main function of A-to-I editing is altering the amino acid sequence of proteins since the translational and transcriptional machineries recognize inosine as guanosine, which can lead to codon changes, changes in splice sites, and elimination of stop codons. However, not many editing sites that change protein structure were found. Those that were found mainly reside in genes coding for brain receptors and ion channels such as glutamate-gated channels.10

With the emerging technology of high-throughput sequencing, detecting A-to-I RNA editing sites became simpler and enabled global analyses of transcriptomes. Screens to detect RNA editing sites in human and in other organisms surprisingly found that A-to-I editing is widespread and occurs in a large fraction of human transcripts.11,12 Most of the newly found editing sites were in noncoding and repetitive regions in the transcriptome, such as in human Alu sequences.13 These findings suggested ADARs and RNA editing have additional functions beyond protein diversification. In addition, studies, which found editing sites in 3’UTR of genes, suggest that RNA editing regulates gene expression by several possible mechanisms such as nuclear retention, promoting degradation, effecting microRNA binding and disturbing translation (reviewed in14).

RNA editing is conserved in metazoans and has been extensively studied in model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Drosophila possesses only a single human ADAR2 like gene, which is needed for normal behavior and neuronal functions.15 C. elegans has two ADAR genes, adr-1 and adr-2, which are expressed in all developmental stages.16 Previous studies have shown that in worms mutated for both ADAR genes, a significant reduction in RNA editing events is seen and the worms exhibit chemotaxis defects, reduced lifespan, and reduced expression of transgenes.16,17

Here, we discuss recently identified functions of A-to-I RNA editing and ADAR proteins in development and in innate immunity, and the notion that RNA editing is highly regulated.

RNA editing is needed for normal development

RNA editing has specific effects on distinct tissues. In humans and mice, most of ADARs’ effects have been seen in the nervous system, from high expression in the brain tissue to changes in neuronal specific proteins.18 In recent studies, different editing pattern of transcripts were also shown in different developmental stages. In some organisms including pigs and chicken, editing levels in specific transcripts were shown to be very low during embryogenesis and to increase in later stages of development even to 100%.19,20 The same pattern of low editing levels in embryonic tissues and stem cells versus adult tissues was also observed in humans.21 Changes in editing levels during development were also shown in Drosophila15 and in C. elegans.22,23 Interestingly, in C. elegans, the global amount of editing levels as well as ADAR expression are highest early in development at the embryonic and L1 developmental stages,23,24 in contrast to humans and mice. The main reservation with these results is that in C. elegans it is very difficult to assay specific tissues and so most of the studies were done on whole worms or whole embryos. Analyzing specific tissues might reveal a different picture.

By studying genes edited at their 3’UTR, we found that some genes are edited only in a specific developmental stage (L4 or embryo), even though they are expressed in the same tissues as ADAR genes in both developmental stages.22 Genes that are edited at their 3’UTR in C. elegans are enriched for neuronal and germline genes,22,25 suggesting a function for RNA editing in these specific tissues. Indeed, worms harboring deletions of ADAR genes have reduced expression of 3’UTR edited genes (Fig. 1, [22]), defects in chemotaxis and a reduced life span.16,17 Another interesting finding was the exclusively embryonic downregulation of pseudogenes and lncRNA expression in ADAR mutants, while the opposite pattern was observed in the L4 developmental stage (Fig. 1, [22]). Upregulation of edited genes was also shown in adult Drosophila ADAR mutants,26 and a correlation between ADAR1 expression and its targets was observed in the human brain.27 Additionally, a downregulation of ADAR1 in human cell culture causes an increase in L1 retrotransposition activity.28

Figure 1. A-to-IRNA editing regulates edited gene and pseudogene expression during development. Summary of the findings of Goldstein et al.22 on the effect of ADAR genes on gene expression in C. elegans. Goldstein et al. focused on 3’UTR edited genes and pseudogenes. They found that 3’UTR edited gene expression is reduced when ADARs are mutated both at the embryo and L4 developmental stages. Pseudogene expression is reduced in ADAR mutants at embryo stage. However, their expression is upregulated in the L4 stage. Mutations in RNAi machinery components rescue pseudogene expression changes in ADAR mutants at the embryo stage but not at L4 stage. The bar charts show the difference in expression of edited genes and pseudogenes in ADAR mutants compared with the expression in wildtype (WT). The difference in expression is shown to scale.

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These results suggest that ADARs alter gene expression and that the effect is specific to developmental stages, tissues and target genes. lncRNAs were shown to be important for cellular maintenance and basic biologic processes and are involved in neurologic diseases.29 Transposons in C. elegans were shown to be silenced by RNA interference (RNAi) in the germline and active in somatic cells.30 Therefore, it is possible that in C. elegans ADARs help in fine tuning lncRNAs expression in specific developmental stages.

The antagonistic relation between RNA editing and RNAi

RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by generating small interfering RNA molecules (siRNAs). One of the roles of RNAi in C. elegans is mediating an anti-viral defense.31,32 There are many genes involved in several RNAi pathways in C. elegans that form a very complex system.33 Both RNAi and RNA editing target dsRNA and were shown to cross paths. Phenotypes observed in C. elegans with mutated ADAR genes are rescued by additional mutations in the RNAi pathway.17,34 microRNAs can be edited as well, and this editing can affect their ability to silence their targets and even direct them to new targets.35,36,37 siRNAs were shown to be able to retain inosine.38 However, it is mainly thought that RNAi components compete with RNA editing on their targets. In C. elegans, specific editing regions in the genome were shown to have enhanced amount of siRNAs in ADAR mutants vs. wildtype.39,40 Pri-microRNAs also undergo RNA editing and this editing can inhibit or promote their being processed by RNAi components.41-43 The downregulation of pseudogenes in ADAR mutated C. elegans embryos was shown to be a result of RNAi, probably because RNA editing targets are available for RNAi processing in ADAR mutants. However, the upregulation of pseudogenes in L4 stage was not affected (Fig. 1, [22]).

Recently, a new function in the innate immune system was found for mammalian RNA editing. ADAR1 can function as a suppressor of the interferon response (for review see [44-46]) and changes in both ADAR1 protein levels and ADAR1 editing function affect the response.47-49 These studies suggest that editing by ADAR1 prevents self-produced dsRNAs that can induce the immune system to trigger the interferon response. Interestingly, ADARs can also have a pro-viral effect depending on the specific virus and host.46

It is tempting to speculate that RNA editing in C. elegans might have the same function as in mammals of repressing the innate immune system. RNAi processes dsRNA mainly in the cytoplasm and can process foreign dsRNA, such as viral RNA. However, it cannot process dsRNA that harbor inosine. Therefore, it is possible that RNA editing, which is mainly a nuclear process, marks dsRNAs and thereby protects them from RNAi when they enter the cytoplasm.

Another question that comes to mind is how ADARs antagonize RNAi in C. elegans. The RNAi system in C. elegans includes different pathways and functions. Two components of the RNAi machinery, rde-1 and rde-4, were shown to affect ADARs’ function. When mutated together with the ADAR genes, the ADAR mutation phenotypes revert to normal.17,34 In addition, it was found that specific regions in the C. elegans genome are enriched in short interfering RNAs (siRNAs) in ADAR mutants vs. wild-type, and that after mutating rde-1 or rde-4, the amount of siRNAs in these regions goes back to wild-type levels.40 However, both proteins, RDE-1 and RDE-4, are probably involved in different RNAi pathways.50 Therefore, the ribonuclease Dicer might be a better candidate for function inhibition by ADAR. Dicer is a multifunctional protein that is essential for most RNAi pathways and is needed for the cleavage of the dsRNA.33,51 Inosines in dsRNA were shown in vitro to inhibit dsRNA cleavage.52 However, this was shown on dsRNAs with abundant editing, while specific, non-clustered editing events might not interfere with the RNAi machinery. In addition, Dicer was shown to interact with human ADAR153 and human ADAR1 and ADAR2 can bind siRNAs to interfere with gene silencing.54 There are several possibilities of how ADARs antagonize Dicer. ADAR might physically bind to dsRNA thus preventing Dicer's access to the dsRNA by simply reducing binding locations (Fig. 2A). This option does not seem likely since ADARs are mainly located in the nucleus and Dicer is mainly a cytoplasmic protein. However, both ADARs and Dicer were shown to be in both compartments.55-59 Additionally, human ADAR1 that is bound to dsRNA can shuttle to the cytoplasm.57 Another possibility is that the deamination from adenosine to inosine itself prevents Dicer from processing the dsRNA, either by Dicer's inability to bind dsRNA that contain inosines (Fig. 2B) or by a reduction in the efficiency of Dicer's binding to dsRNA because of the change in dsRNA's structure (Fig. 2C). These 3 options are not mutually exclusive.

Figure 2. Possible ways in which ADARs prevent Dicer from processing dsRNAs. (A) ADAR enzymes might compete with Dicer on binding to the dsRNA. (B) Dicer might not bind dsRNA with inosines as efficiently as without inosines. (C) The deamination of adenosine into inosine leads to conformational changes of the dsRNA structure, making it a less suitable substrate for Dicer.

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No ADAR is an island

The changes in the transcript's editing patterns during development and in specific tissues while ADAR enzymes expression remains constant suggest that A-to-I RNA editing is tightly regulated (comprehensively reviewed in [60]). In recent years, many regulators of the A-to-I editing process were found, and some of them were shown to interfere with the enzymatic activity of ADAR enzymes. For example, proteins were found that shuttle ADAR proteins to or from the nucleus, and others that affect the structure of ADAR proteins. Other regulators were shown to alter editing levels of specific transcripts, like proteins that compete with ADARs on dsRNA binding locations or disrupt the dsRNA structure.60 Remarkably, ADAR enzymes auto-regulate their function as well. Human ADAR2 and Drosophila ADAR transcripts undergo editing that alter their protein structure and affect their editing ability.61,62 Interestingly, Drosophila ADAR transcript editing is developmentally regulated, with extensively increasing levels of editing from embryo to adult.61 C. elegans ADR-1 does not have deamination activity, but it was shown to affect editing efficiency in specific transcripts by interacting with ADR-2 substrates.63 Most of the studies done so far on C. elegans examined phenotypes and editing or expression changes in worms harboring mutation in both adr-1 and adr-2 genes (e.g., [16,22,23,40,64]). Therefore, studies of these genes separately might reveal if ADR-1 is the regulator that causes developmentally specific editing.

Even though many novel RNA editing regulators were identified, the specific purpose of the regulation and in which tissue or developmental stage the regulation occurs is currently unknown.

Outlook

As our knowledge of the functions of A-to-I RNA editing expands, it becomes clear that editing and ADAR enzymes do not have just one specific role but are important in many phases of the cellular and organismal life. Understanding better how A-to-I editing is regulated, why certain transcripts are edited, and why editing levels vary between tissues and developmental stages are important steps toward elucidating the complex interactions between genome, transcriptome, and development.

Acknowledgments

We thank Orna Ben-Naim Zgayer, Alla Fishman, and Noa Ben-Asher for critical reading of the manuscript. This work was funded by The Israeli Centers of Research Excellence (I-CORE) program, (Center No. 1796/12 to ATL), Israel Cancer Research Fund (ICRF), and the Binational Israel-USA Science Foundation (grant no. 2015091).

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