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Regulatory RNAs discovered in unexpected places

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Recent studies have discovered both small and long noncoding RNAs (ncRNAs) encoded in unexpected places. These ncRNA genes were surprises at the time of their discovery, but many quickly became well‐accepted families of functional regulatory RNA species. Even after years of extensive gene annotation studies using high‐throughput sequencing technologies, new types of ncRNA genes continue to be discovered in unexpected places. We highlight ncRNAs that have atypical structures and that are encoded in what are generally considered ‘junk’ sequences, such as spacers and introns. We also discuss current bottlenecks in the approaches for identifying novel ncRNAs and the possibility that many remain to be discovered. WIREs RNA 2015, 6:671–686. doi: 10.1002/wrna.1309 This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA Turnover and Surveillance > Regulation of RNA Stability Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
Spacer sequences with regulatory activity. (a) An miRNA produced from the fly rRNA ITS1 (internal transcribed spacer 1). A transcribing rDNA unit is shown. The fly rRNA precursor is transcribed as polycistronic RNA containing 18S, 5.8S, 2S, and 28S rRNAs. Transcribed spacer sequences between the mature rRNA sequences are known as ITS. The conserved miRNA hairpin is found in the ITS1 region located between 18S and 5.8S rRNA sequences. The hairpin is processed into mature species by a Drosha‐independent Dicer‐1‐dependent mechanism, and mature miRNA products are loaded to Argonaute effector complexes. The enzyme producing pre‐miRNA hairpins from pre‐rRNAs is currently unknown. (b) A tRNA spacer acting as an sRNA (small regulatory RNA) sponge in E. coli. External transcribed spacers (ETS) of tRNAs are cleaved from tRNA precursors by RNase E during tRNA maturation. In wild‐type bacteria, the iron‐starvation‐responsive sRNAs RyhB and RybB bind to a 3′‐ETS of a Leu tRNA (3′‐ETSleuZ). This binding ensures the complete repression of RyhB/RybB activity under no stress conditions. When the sRNA‐binding site on 3′‐ETSleuZ is mutated, the sRNAs cannot bind 3′‐ETSleuZ, leading to the ectopic activation of sRNA activity under no stress conditions. Under iron starvation, the expression of RyhB and RybB is elevated and 3′‐ETSleuZ can no longer repress the activity of these sRNAs. Therefore, these sRNAs can bind target mRNAs to regulate their expression levels.
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Intron‐split miRNAs. (a) nat‐miRNAs (natural antisense transcript‐miRNAs) in monocots. The gene model illustrates the structure of a MADS box protein/MIR444 locus. The MADS box protein‐coding gene and the MIR444 gene are located on the upper and lower DNA strands, respectively. Two parts of the MIR444 hairpin sequence are far apart in the genomic DNA sequence, but brought closer after the splicing of primary miRNA transcripts. This allows the spliced transcript to be cleaved by the miRNA processing machineries, resulting in the production of mature miR444. On the other hand, because the MADS protein mRNA does not include one part of the MIR444 antisense sequence, this transcript does not form a miRNA‐like hairpin. However, because the mature miRNA product is produced from the region that is perfectly complementary to a part of the MADS protein mRNA (white arrows), the expression of MIR444 results in the downregulation of the MADS protein via direct cleavage of the mRNA mediated by Argonaute proteins. (b) Artificial inc‐miRs (intron‐containing miRNAs) in Caenorhabditis elegans. The heterochronic phenotypes in the lin‐4 mutant were rescued when mutant animals were injected with a plasmid encoding wild‐type lin‐4. Artificial mutant constructs containing intron insertions in the lin‐4 stem region also rescued the phenotype, indicating that miRNAs could be produced even with an intron insertion. When the consensus sequences essential for splicing (GU……..AG) were mutated, the rescue activity was diminished, suggesting that the splicing of inserted introns is essential for efficient production of mature lin‐4 miRNA.
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Limitations in RNA‐seq analyses. (a, b) Examples of artificial removal of RNA‐seq reads by inaccurate reference genome sequences. Reference genomic sequences may have deletions (a) or single‐nucleotide errors/variants (b). These may cause the loss of useful RNA‐seq reads. (c, d) Examples of RNA‐seq reads with posttranscriptionally modified RNA species. RNA can undergo tailing (untemplated nucleotide additions at 3′ ends, shown in (c)) or editing (adenosine deamination resulting in conversion to inosine, shown in (d)). Reads corresponding to modified RNA species are often removed during genome mapping because these reads do not perfectly match with the reference genome sequence. (e) Enrichment of small RNAs with 5′‐monophosphate and 3′‐hydroxyl groups. Because most commonly used protocols for small RNA library construction depend on the ligation of 5′‐ and 3′‐linkers, the resulting libraries will be enriched in small RNAs with 5′‐monophosphate and 3′‐hydroxyl groups. This includes most known small regulatory RNA families. However, there are known RNA species lacking compatible structures at the 5′ or 3′ terminus, such as some worm endo‐siRNAs (with 5′ triphosphate) and piR‐ILs (with 2′–3′ cyclic‐phosphate). These species are depleted in regular small RNA libraries.
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Biogenesis and functions of circRNAs. Diagram showing the biogenesis of circRNAs. Exons and introns are in red/blue and black, respectively. Circles depict the proteins that the RNAs bind.
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Biogenesis and functions of sisRNAs. Diagram showing the biogenesis of sisRNAs. Exons and introns are in red and black, respectively. Circles depict the proteins that the RNAs bind.
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RNA Evolution and Genomics > Computational Analyses of RNA
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA Turnover and Surveillance > Regulation of RNA Stability

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