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The potential of the riboSNitch in personalized medicine

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RNA conformation plays a significant role in stability, ligand binding, transcription, and translation. Single nucleotide variants (SNVs) have the potential to disrupt specific structural elements because RNA folds in a sequence‐specific manner. A riboSNitch is an element of RNA structure with a specific function that is disrupted by an SNV or a single nucleotide polymorphism (SNP; or polymorphism; SNVs occur with low frequency in the population, <1%). The riboSNitch is analogous to a riboswitch, where binding of a small molecule rather than mutation alters the structure of the RNA to control gene regulation. RiboSNitches are particularly relevant to interpreting the results of genome‐wide association studies (GWAS). Often GWAS identify SNPs associated with a phenotype mapping to noncoding regions of the genome. Because a majority of the human genome is transcribed, significant subsets of GWAS SNPs are putative riboSNitches. The extent to which the transcriptome is tolerant of SNP‐induced structure change is still poorly understood. Recent advances in ultra high‐throughput structure probing begin to reveal the structural complexities of mutation‐induced structure change. This review summarizes our current understanding of SNV and SNP‐induced structure change in the human transcriptome and discusses the importance of riboSNitch discovery in interpreting GWAS results and massive sequencing projects. WIREs RNA 2015, 6:517–532. doi: 10.1002/wrna.1291

Experimental validation of the ferritin light chain (FTL) riboSNitch. SHAPE experiments were used to probe the secondary structure of the 5′ UTR of ferritin light chain (FTL 5′ UTR). Where the normalized SHAPE reactivity is high, the residue is not base paired. Where the normalized SHAPE reactivity is low, the residue is paired. Differences in SHAPE reactivity between a wild type and mutant version of the RNA are indicated with a heatmap as indicated: blue indicates positions that are more highly modified (single stranded) in the wild type, and red indicates positions that are more highly modified (single stranded) in the mutant. (a) The wild type (WT, black) and mutant (U22G, cyan) forms of the FTL 5′ UTR show significant differences in secondary structure, as predicted, including the IRE (light purple). U22G is associated with hyperferritinemia cataract syndrome (HCS) and the data indicate that the U22G riboSNitch causes disease by changing the structure of the 5′ UTR and disrupting IRE‐binding protein (IREBP)/iron responsive element (IRE) interactions. (b) The wild type (WT, black) and mutant (G4A, purple) forms of the FTL 5′ UTR have almost identical SHAPE reactivity, suggesting that the RNA structure does not change. G4A is a single nucleotide polymorphism (SNP) that is neither associated with disease nor predicted to change the RNA structure and serves as a negative control for riboSNitch detection. (Reprinted with permission from Ref . Copyright 2012 Cold Spring Harbor Laboratory Press for the RNA Society)
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Visualization of how Single nucleotide variants (SNVs) in the ferritin light chain (FTL) riboSNitch are predicted to shift the RNA structural ensemble toward disrupted iron responsive element (IREs). RNA structures were sampled from the Boltzmann suboptimal ensemble predicted for the human FTL 5′ UTR and clustered using principal component analysis (PCA). The 5′ UTR of ferritin light chain (FTL 5′ UTR) forms three distinct clusters of similar structures (red, blue, green). Structures in the red cluster form canonical IREs whereas those in the blue and green clusters do not. The fraction of the population in each cluster is indicated in black. (a) The WT FTL IRE structural ensemble is dominated by the red cluster, indicating that most of the population contains correctly folded IREs. A representative secondary structure schematic for each cluster is shown (black) with the IRE sequence (purple). The position of SNVs associated with hyperferritinemia cataract syndrome residues is indicated on each schematic (purple dots). IRE‐binding protein (IREBP) (green) would bind a properly folded IRE (purple). (b) The U22G SNV shifts the structural ensemble away from the structures that can bind IREBP (red cluster) to structures with misfolded IREs and is dominated by structures in the green cluster. (c) The A56U SNV also shifts the structural ensemble toward misfolded IREs that cannot bind IREBP. (Reprinted with permission from Ref . Copyright 2012 Cold Spring Harbor Laboratory Press for the RNA Society)
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Single nucleotide polymorphisms (SNPs) can affect protein binding through sequence, local, or distant structural changes. (a) The IRE‐binding protein (IREBP)/iron responsive element (IRE) interaction in ferritin light chain (FTL) requires both sequence and structural elements. Schematic of productive interaction between IREBP (green) and the IRE (purple) in the human 5′ UTR of ferritin light chain (FTL 5′ UTR) (secondary structure representation in black). (b) The IREBP (green)/IRE (purple) interaction in FTL can be disrupted by mutating a residue (purple dot) that does not contact the protein, but significantly changes the local structure of the IRE. Mutation of any residue that shifts the structure of the IRE could affect binding through this mechanism, including residues that are not actually in the IRE itself. These types of effects are more difficult to predict because they involve accurate secondary structure prediction as well as simple sequence analysis. Secondary structure schematics of the FTL 5′ UTR are based on prediction and experimental data. (c) The IREBP (green)/IRE (purple) interaction is weakened by mutating a nucleotide (red dot) that makes sequence‐specific interactions with the protein in the loop region of the IRE even if the mutation does not change the overall structure of the IRE. Mutation of any of the loop and bulge positions that make sequence‐specific contacts (red in D) will affect binding through this mechanism. (d) Crystal structure of the rabbit IREBP in complex with frog ferritin H IRE‐RNA (3SNP, Ref ). The IREBP protein (green) has base‐specific contacts with the IRE residues in the loop and bulge (red), but nucleotides that create the helical structure (purple) of the IRE also contribute to recognition. This figure was created using PyMOL. (e) Schematic of the secondary structure of the end of exon 7 (orange) and the intron in survival motor neuron 2 (SMN2). Protein‐binding sites are shown in red (hnRNP A1/A2B1) and blue (TIA1). Protein binding and exon inclusion are significantly impacted by the long‐range interaction shown in gray. This figure was reproduced with modifications. This suggests that riboSNitches might also impact function by changing long‐range structural elements.
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Changes in RNA structure could contribute to regulation of gene expression in a variety of ways. As RNA structure is vital for function, changes in RNA structure could either promote or inhibit gene expression. A conformational change could alter diverse processes including splicing, export, localization, translation initiation or elongation, or decay. Conformational changes may also have a significant role in RNA‐based mechanisms of regulation that involve noncoding RNA (ncRNA) such as microRNAs (miRNAs) or long noncoding RNAs (lncRNAs). A given riboSNitch need only impact a single event or interaction during its lifetime to have a real impact on gene expression. Elucidating the impact of riboSNitches on the transcriptome and genetic regulation will be vital to a mechanistic understanding of disease and the future of personalized medicine.
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RNA component of mitochondrial RNA processing endoribonuclease (RMRP) forms different structures that are differentially processed into deleterious microRNAs (miRNAs). (a) Secondary structure of RMRP compatible with the experimental SHAPE data. SHAPE reactivity is indicated by color as shown in the heat map: areas of high reactivity (single stranded) are red; areas of low reactivity (base paired) are blue. RMRP‐S1 and S2 (red bars) and nucleotides where SNVs are found in CHH patients are indicated (gray circles). (b) Predicted structures based on SHAPE data (blue) and previously published conservation and probing data (yellow) are quite different, indicating heterogeneity in RMRP structure. The R‐CHIE R program was used to represent base pairs as arcs. Pseudoknots occur wherever arcs cross; in this case, in the yellow, but not the blue arc diagram. The other major difference is the formation of the alternative P2 helix (Alt‐P2) in the blue structure, which resolves the pseudoknot. Taken together, the two predictions are consistent with the hypothesis that RMRP adopts at least two alternative conformations, but it is the experimentally observed blue structure that is more susceptible to Dicer cleavage and processing. (Reprinted with permission from Ref . Copyright 2014 Oxford University Press)
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Analysis of photoactivatable‐ribonucleoside‐enhanced crosslinking and immunoprecipitation (PAR‐CLIP) and expression Quantitative Trait Loci (eQTLs) data indicate a bias toward RNA–protein binding interactions in 3′ untranslated regions (UTRs). (a and c) PAR‐CLIP(a) and eQTL (c) sites are rarely intronic (blue), but are usually exonic (purple). All proteins with PAR‐CLIP data at the time of analysis were studied; the name of the protein is indicated next to the bar. Proteins with known roles in splicing (ELAVL1, QK1, and FUS) have more intronic sites. (b and d) PAR‐CLIP (b) and eQTL (d) sites are also biased to the 3′ UTR (green) as opposed to the 5′ UTR (blue) or coding sequence (CDS) (red). For eQTLs, these effects are more prominent when linkage disequilibrium is taken into account and positions that could directly affect the transcription start site are removed.
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
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