Abstract
The dynamic structure of RNA plays a central role in post-transcriptional regulation of gene expression such as RNA maturation, degradation, and translation. With the rise of next-generation sequencing, the study of RNA structure has been transformed from in vitro low-throughput RNA structure probing methods to in vivo high-throughput RNA structure profiling. The development of these methods enables incremental studies on the function of RNA structure to be performed, revealing new insights of novel regulatory mechanisms of RNA structure in plants. Genome-wide scale RNA structure profiling allows us to investigate general RNA structural features over 10s of 1000s of mRNAs and to compare RNA structuromes between plant species. Here, we provide a comprehensive and up-to-date overview of: (i) RNA structure probing methods; (ii) the biological functions of RNA structure; (iii) genome-wide RNA structural features corresponding to their regulatory mechanisms; and (iv) RNA structurome evolution in plants.
RNA secondary structure plays many essential roles in RNA synthesis, metabolism, and regulatory pathways (; ). Previous efforts to determine RNA structure depended on classical and time-consuming techniques, such as nuclear magnetic resonance spectroscopy (NMR), X-ray crystallography, and cryo-electron microscopy (Table 1) (). However, these methods yielded data limited to a few key RNAs with comparatively short length (less than 200 nt) and high abundance (∼1 μmol).
Table 1
| Experiments | Capabilities | In silico, in vitro, or in vivo | Application | Reaction conditions | Reference | |
|---|---|---|---|---|---|---|
| Targeted individual RNA structure probing | NMR; X-ray crystallography; Cryo-electron microscopy | Determine the three-dimensional structure at high resolution | In vitro | Ribosome, HIV | Specific buffer conditions | |
| Gel-based enzymatic and chemical probing | Determine the RNA secondary structure of high abundant RNAs up to 200 nt length | In vitro or in vivo | E. coli | Specific buffer conditions/cellular conditions | ; | |
| SHAPE-CE | Determine the RNA secondary structure of high abundant RNAs up to 400 nt length | In vitro | Arabidopsis | Specific buffer conditions | ||
| DMS/SHAPE-LMPCR | Determine the RNA secondary structure of low abundant RNAs | In vivo | Arabidopsis, human | Cellular conditions | ||
| SHAPE-Seq | Determine the RNA secondary structure of long RNAs | In vitro | RNase P pT181 sense RNA | Specific buffer conditions | ||
| SHAPE-MaP; DMS-MaP | Determine the RNA secondary structure of low abundant and long RNAs | In vitro or in vivo | TPP, HIV Yeast, human | Specific buffer conditions/cellular conditions | ; ; | |
| Genome-wide RNA structure profiling | FragSeq; PARS; PARTE; PIP-seq | Determine genome-wide in vitro RNA secondary structure with enzymatic probing | In vitro | Mouse Yeast, human Arabidopsis | Specific buffer conditions | ; ; ; , ; ; |
| CIRS-seq | Determine genome-wide in vitro RNA secondary structure with chemical probing | In vitro | Mouse | Specific buffer conditions | ||
| DMS-seq; Structure-seq; Mod-seq | Determine genome-wide in vivo RNA secondary structure with chemical probing | In vivo | Arabidopsis Yeast Oryza sativa | Cellular conditions | ; ; ; | |
| icSHAPE | Determine genome-wide in vivo RNA secondary structure with chemical probing | In vivo | Mouse | Cellular conditions |
RNA structure probing methods for both individual RNAs and at the genome-wide scale.
More recently, enzymatic and chemical structure probing methods have been developed to routinely and efficiently obtain structural information of individual RNAs. Ribonucleases (RNase) cleave either single-stranded (ss) RNA regions or double-stranded (ds) RNA regions to indicate RNA base-pairing status. The most commonly used enzymatic probing reagents include RNase V1 (for dsRNA), RNase S1 (for ssRNA), RNase A (for C/U in ssRNA), and RNase T1 (for G in ssRNA) (). The RNase-based RNA structure probing method has been used extensively in studying RNA structure with less toxicity, but with the limitation of cell permeability (). For chemical probing, two main types of chemical reagent can be used. One modifies the Watson-Crick base-pairing face on the nucleobase, as a direct measure of single-strandedness. Dimethyl sulfate (DMS) is one of the most commonly used nucleobase probing reagents as it easily penetrates the cell, a pre-requisite for in vivo chemical probing (). Another example is 1-cyclohexyl-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate (CMCT), which targets the unpaired N3 position of uracil and the unpaired N1 position of guanine (); while 3-ethoxy-1,1-dihydroxy-2-butanone (kethoxal) attacks the unpaired N1 and unpaired exocyclic amine positions of guanine (). Among these reagents, DMS is predominantly used to probe RNA structures in different organisms (; ; ; ). The other type of chemical reagent modifies the ribose, by selective 2′-hydroxyl acylation and which can be analyzed by primer extension (SHAPE) (; ). A particular advantage of SHAPE is that it generates structural information for all four nucleotides at the same time.
Polyacrylamide gel electrophoresis (PAGE) assays were traditionally used to measure the modified pattern of both enzymatic and chemical reactions (; ; ). However, these gel-based assays were limited to highly abundant and short (less than 200 nt) RNAs. The application of capillary electrophoresis (CE) improved the detection limits of both the length (up to 400 nt) and the abundance of RNA (Table 1) (). A recent application of CE on Arabidopsis thaliana long non-coding RNA (lncRNA), COOLAIR, revealed the remarkable complexity of RNA structure up to 750 nt (). A further improved method on probing sensitivity, DMS/SHAPE-LMPCR, was developed in Arabidopsis thaliana (Table 1). This method achieved “attomole” sensitivity allowing RNA structure probing of low abundance RNAs in living cells (). By subsequently combining the action of DMS with next-generation sequencing high-depth RNA structural information of very long RNAs was achieved (; ). For instance, the structural information of over 18 kb lncRNA, Xist, was fulfilled in a single experiment (). The development of these approaches has significantly improved the sensitivity and resolution for probing individual RNA structure both in vitro and in vivo. The capability for single nucleotide-resolution quantitative measurements on any RNA down to 1 attomole and up to 18 kb enables efficient functional investigation of RNA structure in biological processes.
Genome-wide RNA structure profiling was initially achieved by coupling enzymatic probing with next-generation sequencing, PARS (parallel analysis of RNA structure) (Table 1). It was developed in yeast by measuring the catalytic activity of two enzymes, RNase V1 (for dsRNA) and S1 (for ssRNA) (). This method was extended in Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens (,; ). An enhanced method, PIP-seq (protein interaction profiling sequencing), complements RNA–protein interaction information with in vitro RNA structure profiling (Table 1) (; ; ). A further improvement on genome-wide scale RNA structure profiling extended to living cells and addressed native RNA folding status. By harnessing the cell permeability of DMS, the first genome-wide in vivo RNA structure profiling method, Structure-seq, was developed in Arabidopsis (, ) in parallel with DMS-seq and Mod-seq in yeast (; ) (Table 1). Both methods reveal in vivo RNA structures are more single-stranded than in vitro and in silico computational predicted RNA structures. Use of the Structure-seq method was recently extended to rice (). A follow-up genome-wide in vivo RNA structure profiling method, icSHAPE (in vivo click SHAPE), was developed in mouse by using the SHAPE chemical reagent with the power of four-nucleotide probing (Table 1) (). In addition to measuring reverse transcription stopping, chemical modification can also be determined by mutational profiling (Table 1) (; ; ).
These powerful genome-wide methods can provide an accurate and quantitative in vivo RNA structure map over tens of thousands of RNA with single nucleotide-resolution. These technological advances create an unprecedented scale for the in-depth study of the global impact of RNA structure in gene regulation. For example, regulatory RNAs are able to act as a master regulator in gene expression. In general, these regulatory RNAs directly turn on or off gene expression by altering RNA secondary structure. A recent study of RNA structure characterization on a range of regulatory RNAs in Arabidopsis is illustrated below (Figure 1).
FIGURE 1
A riboswitch is a type of regulatory RNA that contains specific RNA structure segments, which can change conformation depending on specific ligand binding, e.g., metabolites. A well-studied example of a riboswitch is the vitamin B1 derivative thiamin pyrophosphate (TPP), which resides in the 3′ UTR region of the thiamin biosynthetic gene THIC () (Figure 1A). With a low TPP concentration, the 3′ end processing of THIC mRNA results in a short 3′ UTR that permits high expression of the THIC gene. Conversely, with a high TPP concentration, TPP binds directly with the 3′ end of the RNA and induces a structural change that prevents splicing. This results in a long 3′ UTR inducing RNA degradation, subsequently reducing THIC gene expression (). Unlike riboswitches in bacteria that control translation through a structural change in the 5′ UTR, plants may have evolved a diverse and more complicated alternative 3′ end processing mechanism in order to cope with a large number of metabolites ().
Not only are some metabolites able to bind to specific RNA structures to regulate their synthesis pathways, but some are also able to regulate their own expression levels. A plant conserved pre-mRNA of transcription factor IIIA (TFIIIA) contains a 5S rRNA mimic structural element in one of its exons () (Figure 1C). When ribosomal protein L5 binds to this 5S rRNA mimic, it triggers exon skipping in TFIIIA mRNA to control TFIIIA levels (). This ribosomal protein–mRNA interaction provides a new-found class of RNAs regulating alternative splicing to control the protein level.
Furthermore, specific RNA structural motifs such as G-quadruplexes (GQS) also play an important role in gene expression regulation. RNA GQSs are typically more stable in the presence of potassium or sodium. Tens of thousands of putative GQSs were identified in Arabidopsis and other plant species (). A recent study reported the first highly-conserved plant RNA GQS located in the 5′ UTR of ATAXIA TELANGIECTASIA-MUTATED AND RAD3-RELATED (ATR), inhibiting its translation when forming stable GQS structures () (Figure 1E). Interestingly, potassium concentrations in plant cells can dramatically increase under drought stress (). Thus, GQS structural motifs in plants may specifically act as a regulator in response to abiotic stress, such as drought and salinity.
Long non-coding RNAs have also been shown as important regulatory RNAs involved in various biological processes. The study of lncRNA structures has been limited in the past due to their long length and low abundance. Advances in probing methods has enabled the highly-conserved plant lncRNA COOLAIR structure to be determined by chemical profiling with CE (). COOLAIR is a key regulator of a major plant developmental gene FLC (FLOWERING LOCUS C), in response to vernalisation. The distal COOLAIR isoform in Arabidopsis (Figure 1) is highly-structured with numerous secondary structural motifs, an intricate multi-way junction, and two unusual asymmetric 5′ internal loops () (Figure 1B). Interestingly, a single nucleotide polymorphism (SNP) in the natural variation accession, Var2-6, is able to change the structure to affect the RNA stability, resulting in a late-flowering phenotype in Var2-6 (). RNA secondary structure determination has progressed our understanding of the structure–function relationship of lncRNAs for the first time in plants.
The other well-known regulatory RNAs, miRNAs, also heavily rely on RNA structure for their regulatory functions (). The double-stranded region of miRNA precursors (pri-miRNAs) are recognized and processed by Dicer protein, an RNase III-like enzyme (). Previous studies in plants on both individual miRNA precursors and genome-wide assessment of pri-miRNA processing products confirmed that different structure determinants within pri-miRNAs compete for the processing machinery (; ) (Figure 1D). A recent RNA structure characterization study by NMR shows the upper stem of a double-stranded region of pri-miR156 is important for Dicer processing at different temperatures, that substantiates the structure-determined Dicer processing feature (). After Dicer processing, an Argonaute (AGO) protein will recognize the processed duplex miRNA to target mRNA containing complementary sequence for either RNA cleavage or translational inhibition (). Genome-wide in vitro RNA structure profiling in Arabidopsis revealed a less structured pattern in miRNA target sites that indicates the relationship between miRNA target efficiency and the single-stranded structural feature ().
Apart from these studies on regulatory RNAs, recent genome-wide research also reveals the general role of mRNA structure in a variety of post-transcriptional regulations such as RNA maturation, RNA stability, RNA location and translation.
Alternative splicing is an important process in RNA maturation. More than 40% of Arabidopsis genes possess alternative spliced isoforms (). The first in vivo RNA structure profiling in Arabidopsis revealed a significantly less structural pattern in the 40 nt region upstream of the 5′ splice site for unspliced events (including exon skipping and intron retention) (). PIP-seq further revealed that this kind of structural pattern results in more RNA-protein interactions in Arabidopsis nuclei (; ). Interestingly, PIP-seq also found the robust structure at the 3′ splice site is responsible for more protein interactions (; ). Thus, these RNA structural features indicate an important role of RNA structure in regulating alternative splicing.
Another RNA maturation process is alternative polyadenylation (APA) that is found in over 60% of mRNAs in Arabidopsis (). In vivo RNA structure profiling shows a strong structural pattern in the U- and A-rich upstream region of the cleavage site as well as a single-stranded region at the cleavage site (). These patterns may correlate with the recognition of endonucleases for regulating APA. Further study using PIP-seq shows more protein bound up- and downstream of the APA cleavage site as compared to constitutive polyadenylation events (). However, APA sites do not exhibit altered in vitro RNA secondary structure compared to constitutive sites (). This suggests there may be different effects of RNA structure on both protein binding and cleavage activity, that warrant closer investigation.
In addition to RNA maturation, the relationship between RNA structure and RNA degradation has also been uncovered by in vitro RNA structurome analysis in Arabidopsis. Unlike yeast, highly-structured mRNAs are more likely to be degraded in Arabidopsis, probably via specific siRNA processing ().
An interesting study on RNA mobility in plants shows that a stem-bulge-stem-loop tRNA-derived structural motif is sufficient to mediate mRNA transport. A large number of mRNAs containing this motif can be moved through graft junction (). Thus, RNA structure might also affect intercellular communication across plants.
Another major impact of RNA structure is its regulatory role in translation. Both in vitro and in vivo RNA structure profiling show a single-stranded region upstream of the start codon that might facilitate ribosome initiation (; ). Moreover, a triplet periodic trend is observed in the CDS region but not in UTRs. These structure patterns are obvious in mRNAs with high translation efficiency and are absent in those with low translation efficiency (). This implies that ribosomes may recognize RNA secondary structure as an additional layer of information alongside sequence content.
Additionally, RNA structure is also strongly associated with RNA methylation sites and RNA binding protein (RBP) sites. For example, N6-methylation of adenosine alters the stability of the A⋅U pair (). Cellular RNAs show a decrease in base pairing around sites of m6A when they were methylated (). Recent genome-wide studies indicate that the N6-methyladenosine (m6A) prefers single-stranded conformations rather than double-stranded structures (). A genome-wide study in Arabidopsis shows an enrichment of m6A around the start codon, stop codon and 3′ UTR region (). Interestingly, this enrichment region of m6A is well-correlated with the single-stranded region identified in RNA structure profiling (; ). A study of the RNA structurome in rice also confirmed that higher m6A modification sites tend to have less RNA structure (). This indicates that m6A association may alter RNA structure to more single-strandedness to facilitate gene regulation.
Another key player in post-transcriptional regulations is RBP. Unlike DNA binding protein, RBP associates not only with the primary sequence motifs, but also RNA structural patterns. A recent study combining genome-wide RBP profiling and RNA secondary structure profiling shows that RBP binding sites tend to be more single-stranded (). Interestingly, a nuclear PIP-seq study confirms that both RNA secondary structure and RBP binding sites show quite different patterns between hair and non-hair cells in plants (). This suggests that cell-type-specific RNA structure and RBP binding may be a new regulatory mechanism during plant development.
From an evolutionary perspective, the conservation and diversity of RNA structurome between species remains poorly understood. A recent study compared, for the first time, the conservation and divergence of in vivo RNA structurome between plant species, to assess the evolutionary adaptation of RNA structure (). This study found that in vivo RNA secondary structure conservation does not correlate with sequence conservation between rice and Arabidopsis. The conservation and divergence in both sequence and RNA secondary structure are highly relevant with specific biological processes (). This indicates evolutionary selection not only modifies sequence, but also alters RNA structure to regulate gene expression. This in turn suggests that RNA secondary structure may serve a different layer of selection to sequence in plants.
Recent methodology advances have overcome previous limitations of both low-throughput and in vitro conditions for studying RNA secondary structure. These new methods, with single-nucleotide resolution, genome-wide scale and high sensitivity, significantly accelerate the study of in vivo RNA structure and associated biological functions. Plants are more sensitive than animals to varying environmental conditions, such as changes in temperature, salinity, acidity, and heavy metal concentrations (). These factors are able to affect RNA folding (; ; ). By applying these new RNA structure analysis methods under a range of environmental conditions, we will be able to determine how RNA structure alters in response to these changes. By integrating RNA structure profiling with mutagenesis assays and phenotypic analysis, the relationship between RNA structure and biological function can be investigated in greater details. Extending analyses to other plant species provides scope for exploring evolutionary selection at the RNA structure level. It is notable that this new era of studying RNA secondary structure provides unprecedented opportunity for discovering novel regulatory mechanisms of gene expression in plants.
Statements
Author contributions
XY, MY, HD, and YD wrote the manuscript. MY produced the figure. XY, HD, and YD made the corrections. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
Funding
This study was supported by the Biotechnology and Biological Sciences Research Council (Grant No. BB/L025000/1 to XY, HD, and YD) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant No. 680324 to MY and YD).
Acknowledgments
We apologize to authors whose work has not been cited here, because of the limitations associated with the review format.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
RNA structurome, gene regulation, regulatory RNAs, RNA structure and function, plant RNA biology
Citation
Yang X, Yang M, Deng H and Ding Y (2018) New Era of Studying RNA Secondary Structure and Its Influence on Gene Regulation in Plants. Front. Plant Sci. 9:671. doi: 10.3389/fpls.2018.00671
Received
28 February 2018
Accepted
02 May 2018
Published
22 May 2018
Volume
9 - 2018
Edited by
Dora Szakonyi, Instituto Gulbenkian de Ciência (IGC), Portugal
Reviewed by
Cuncong Zhong, University of Kansas, United States; Carmen Hernandez, Instituto de Biología Molecular y Celular de Plantas (IBMCP), Spain; Aleksandar Spasic, University of Rochester, United States
Updates
Copyright
© 2018 Yang, Yang, Deng and Ding.
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*Correspondence: Yiliang Ding, yiliang.ding@jic.ac.uk
†These authors have contributed equally to this work.
This article was submitted to Plant Cell Biology, a section of the journal Frontiers in Plant Science
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