The evolution of RNA structural probing methods: From gels to next‐generation sequencing

Advanced Review

Valerie Vivet‐Boudou, Redmond P. Smyth, Roland Marquet, Jean‐Christophe Paillart, Elodie Mailler

Published Online: Nov 28 2018

DOI: 10.1002/wrna.1518

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RNA molecules are important players in all domains of life and the study of the relationship between their multiple flexible states and the associated biological roles has increased in recent years. For several decades, chemical and enzymatic structural probing experiments have been used to determine RNA structure. During this time, there has been a steady improvement in probing reagents and experimental methods, and today the structural biologist community has a large range of tools at its disposal to probe the secondary structure of RNAs in vitro and in cells. Early experiments used radioactive labeling and polyacrylamide gel electrophoresis as read‐out methods. This was superseded by capillary electrophoresis, and more recently by next‐generation sequencing. Today, powerful structural probing methods can characterize RNA structure on a genome‐wide scale. In this review, we will provide an overview of RNA structural probing methodologies from a historical and technical perspective. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Methods > RNA Analyses in vitro and In Silico RNA Methods > RNA Analyses in Cells

Schematic representation of RNA structural motifs. The main folding motifs are highlighted: Three‐way junction (green), mismatch (light blue), internal loop (purple), bulge (red), apical loop (pink), single‐stranded region (dark pink), and pseudoknot (gold)

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3′ and 5′ adaptors addition during cDNA library preparation. (a) In the intermolecular ligation pathway, the 5′ adaptor (blue) is linked at the 5′ end of the RT primer (red) complementary to the RNA 3′ end. Once the cDNA (dashed red) has been obtained, the 3′ adaptor (green) is linked to the 3′ end of the neo‐synthetized cDNA. The arrows on the cDNA indicate the direction of the sequence. (b) In the intramolecular ligation pathway, both 5′ (blue) and 3′ (green) adaptors are linked to the 5′ end of the RT primer (red). Once the cDNA (dashed red) has been obtained, the 5′ end of the 3′ adaptor and the 3′ end of cDNA are ligated together to give a circular cDNA. The circular cDNA is digested at a specific locus between the 5′ adaptor and the 3′ adaptor to give the desired cDNA library with the 3′ and 5′ adaptors flanking the cDNA of interest. Note that the sequence of the 3′ adaptor linked to the RT primer has to be carefully chosen since this sequence is the reverse of the final 3′ adaptor sequence obtained after intramolecular ligation/digestion steps

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Summary of the current high‐throughput methods to probe RNA structure. These methods have been designed to cover an entire genome or to study a low‐abundance RNA population, using chemical/enzymatic probes. The originality of each approach resides on the reactivity readout method and the protocol to create the sequencing library. Bioinformatic pipelines are usually developed to finally convert sequencing raw data into reactivity

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Synthetic representation of conventional RNA probing methods. (a) Direct probing of small RNAs by chemical or enzymatic strand scission and PAGE visualization of labeled RNA fragments. (b) Indirect probing of small and long RNAs by chemical modification or strand scission followed by reverse transcription of radio‐labeled primers, PAGE visualization of cDNA. Reactivity quantification and RNA fold are manually performed. (c) Same as panel (b), but with fluorescently labeled primers, cDNA separation and visualization are performed by capillary electrophoresis and reactivity quantification/RNA fold are automatized

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RNA probing reagents. (a) Common enzymatic probes with their cleavage site on single‐stranded (left) or double‐stranded (right) RNA. The p indicates the phosphate group (terminal or linkage), A is for adenosine, G for guanosine, Py for pyrimidine nucleosides, and N for any nucleoside. The arrow indicates the cleavage site and the nature of the obtained fragment (3′ or 5′ phosphate). (b) Target position of chemical probes. Hydroxyl radicals are generally generated by Fenton reagents (H₂O₂, Fe(EDTA), and sodium ascorbate) and Pb(II) is from lead acetate. The hydrogen bonds are drawn to illustrate the Watson‐crick face of the bases but do not indicate that the nucleotides are paired. (c) Reaction time scale for the main chemical probes reported in the literature. These values are dependent on probe concentration and reaction temperature. For SHAPE probes, the reaction time corresponds to five times the half‐life. (d) Chemical structure of the probes. (e) Structure of the chemical probes of the SHAPE family designed to perform a streptavidin selection once they have been coupled to RNA and biotin

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