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1
Kiening, Ochsenreiter, Hellinger, Rattei, Hofacker, and Frishman. "Conserved Secondary Structures in Viral mRNAs." Viruses 11, no. 5 (April 29, 2019): 401. http://dx.doi.org/10.3390/v11050401.
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RNA secondary structure in untranslated and protein coding regions has been shown to play an important role in regulatory processes and the viral replication cycle. While structures in non-coding regions have been investigated extensively, a thorough overview of the structural repertoire of protein coding mRNAs, especially for viruses, is lacking. Secondary structure prediction of large molecules, such as long mRNAs remains a challenging task, as the contingent of structures a sequence can theoretically fold into grows exponentially with sequence length. We applied a structure prediction pipeline to Viral Orthologous Groups that first identifies the local boundaries of potentially structured regions and subsequently predicts their functional importance. Using this procedure, the orthologous groups were split into structurally homogenous subgroups, which we call subVOGs. This is the first compilation of potentially functional conserved RNA structures in viral coding regions, covering the complete RefSeq viral database. We were able to recover structural elements from previous studies and discovered a variety of novel structured regions. The subVOGs are available through our web resource RNASIV (RNA structure in viruses; http://rnasiv.bio.wzw.tum.de).
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Diviney, Sinéad, Andrew Tuplin, Madeleine Struthers, Victoria Armstrong, Richard M. Elliott, Peter Simmonds, and David J. Evans. "A Hepatitis C Virus cis-Acting Replication Element Forms a Long-Range RNA-RNA Interaction with Upstream RNA Sequences in NS5B." Journal of Virology 82, no. 18 (July 9, 2008): 9008–22. http://dx.doi.org/10.1128/jvi.02326-07.
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ABSTRACT The genome of hepatitis C virus (HCV) contains cis-acting replication elements (CREs) comprised of RNA stem-loop structures located in both the 5′ and 3′ noncoding regions (5′ and 3′ NCRs) and in the NS5B coding sequence. Through the application of several algorithmically independent bioinformatic methods to detect phylogenetically conserved, thermodynamically favored RNA secondary structures, we demonstrate a long-range interaction between sequences in the previously described CRE (5BSL3.2, now SL9266) with a previously predicted unpaired sequence located 3′ to SL9033, approximately 200 nucleotides upstream. Extensive reverse genetic analysis both supports this prediction and demonstrates a functional requirement in genome replication. By mutagenesis of the Con-1 replicon, we show that disruption of this alternative pairing inhibited replication, a phenotype that could be restored to wild-type levels through the introduction of compensating mutations in the upstream region. Substitution of the CRE with the analogous region of different genotypes of HCV produced replicons with phenotypes consistent with the hypothesis that both local and long-range interactions are critical for a fundamental aspect of genome replication. This report further extends the known interactions of the SL9266 CRE, which has also been shown to form a “kissing loop” interaction with the 3′ NCR (P. Friebe, J. Boudet, J. P. Simorre, and R. Bartenschlager, J. Virol. 79:380-392, 2005), and suggests that cooperative long-range binding with both 5′ and 3′ sequences stabilizes the CRE at the core of a complex pseudoknot. Alternatively, if the long-range interactions were mutually exclusive, the SL9266 CRE may function as a molecular switch controlling a critical aspect of HCV genome replication.
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Tuplin, A., D. J. Evans, and P. Simmonds. "Detailed mapping of RNA secondary structures in core and NS5B-encoding region sequences of hepatitis C virus by RNase cleavage and novel bioinformatic prediction methods." Journal of General Virology 85, no. 10 (October 1, 2004): 3037–47. http://dx.doi.org/10.1099/vir.0.80141-0.
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There is accumulating evidence from bioinformatic studies that hepatitis C virus (HCV) possesses extensive RNA secondary structure in the core and NS5B-encoding regions of the genome. Recent functional studies have defined one such stem–loop structure in the NS5B region as an essential cis-acting replication element (CRE). A program was developed (structur_dist) that analyses multiple rna-folding patterns predicted by mfold to determine the evolutionary conservation of predicted stem–loop structures and, by a new method, to analyse frequencies of covariant sites in predicted RNA folding between HCV genotypes. These novel bioinformatic methods have been combined with enzymic mapping of RNA transcripts from the core and NS5B regions to precisely delineate the RNA structures that are present in these genomic regions. Together, these methods predict the existence of multiple, often juxtaposed stem–loops that are found in all HCV genotypes throughout both regions, as well as several strikingly conserved single-stranded regions, one of which coincides with a region of the genome to which ribosomal access is required for translation initiation. Despite the existence of marked sequence conservation between genotypes in the HCV CRE and single-stranded regions, there was no evidence for comparable suppression of variability at either synonymous or non-synonymous sites in the other predicted stem–loop structures. The configuration and genetic variability of many of these other NS5B and core structures is perhaps more consistent with their involvement in genome-scale ordered RNA structure, a structural configuration of the genomes of many positive-stranded RNA viruses that is associated with host persistence.
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Thurner, Caroline, Christina Witwer, Ivo L. Hofacker, and Peter F. Stadler. "Conserved RNA secondary structures in Flaviviridae genomes." Journal of General Virology 85, no. 5 (May 1, 2004): 1113–24. http://dx.doi.org/10.1099/vir.0.19462-0.
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Presented here is a comprehensive computational survey of evolutionarily conserved secondary structure motifs in the genomic RNAs of the family Flaviviridae. This virus family consists of the three genera Flavivirus, Pestivirus and Hepacivirus and the group of GB virus C/hepatitis G virus with a currently uncertain taxonomic classification. Based on the control of replication and translation, two subgroups were considered separately: the genus Flavivirus, with its type I cap structure at the 5′ untranslated region (UTR) and a highly structured 3′ UTR, and the remaining three groups, which exhibit translation control by means of an internal ribosomal entry site (IRES) in the 5′ UTR and a much shorter less-structured 3′ UTR. The main findings of this survey are strong hints for the possibility of genome cyclization in hepatitis C virus and GB virus C/hepatitis G virus in addition to the flaviviruses; a surprisingly large number of conserved RNA motifs in the coding regions; and a lower level of detailed structural conservation in the IRES and 3′ UTR motifs than reported in the literature. An electronic atlas organizes the information on the more than 150 conserved, and therefore putatively functional, RNA secondary structure elements.
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Sperschneider, Jana, Amitava Datta, and Michael J. Wise. "Predicting pseudoknotted structures across two RNA sequences." Bioinformatics 28, no. 23 (October 8, 2012): 3058–65. http://dx.doi.org/10.1093/bioinformatics/bts575.
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Abstract Motivation Laboratory RNA structure determination is demanding and costly and thus, computational structure prediction is an important task. Single sequence methods for RNA secondary structure prediction are limited by the accuracy of the underlying folding model, if a structure is supported by a family of evolutionarily related sequences, one can be more confident that the prediction is accurate. RNA pseudoknots are functional elements, which have highly conserved structures. However, few comparative structure prediction methods can handle pseudoknots due to the computational complexity. Results A comparative pseudoknot prediction method called DotKnot-PW is introduced based on structural comparison of secondary structure elements and H-type pseudoknot candidates. DotKnot-PW outperforms other methods from the literature on a hand-curated test set of RNA structures with experimental support. Availability DotKnot-PW and the RNA structure test set are available at the web site http://dotknot.csse.uwa.edu.au/pw. Contact janaspe@csse.uwa.edu.au Supplementary information Supplementary data are available at Bioinformatics online.
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Gao, William, Thomas A. Jones, and Elena Rivas. "Discovery of 17 conserved structural RNAs in fungi." Nucleic Acids Research 49, no. 11 (June 4, 2021): 6128–43. http://dx.doi.org/10.1093/nar/gkab355.
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Abstract Many non-coding RNAs with known functions are structurally conserved: their intramolecular secondary and tertiary interactions are maintained across evolutionary time. Consequently, the presence of conserved structure in multiple sequence alignments can be used to identify candidate functional non-coding RNAs. Here, we present a bioinformatics method that couples iterative homology search with covariation analysis to assess whether a genomic region has evidence of conserved RNA structure. We used this method to examine all unannotated regions of five well-studied fungal genomes (Saccharomyces cerevisiae, Candida albicans, Neurospora crassa, Aspergillus fumigatus, and Schizosaccharomyces pombe). We identified 17 novel structurally conserved non-coding RNA candidates, which include four H/ACA box small nucleolar RNAs, four intergenic RNAs and nine RNA structures located within the introns and untranslated regions (UTRs) of mRNAs. For the two structures in the 3′ UTRs of the metabolic genes GLY1 and MET13, we performed experiments that provide evidence against them being eukaryotic riboswitches.
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Rivas, Elena, Jody Clements, and Sean R. Eddy. "Estimating the power of sequence covariation for detecting conserved RNA structure." Bioinformatics 36, no. 10 (February 7, 2020): 3072–76. http://dx.doi.org/10.1093/bioinformatics/btaa080.
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Abstract Pairwise sequence covariations are a signal of conserved RNA secondary structure. We describe a method for distinguishing when lack of covariation signal can be taken as evidence against a conserved RNA structure, as opposed to when a sequence alignment merely has insufficient variation to detect covariations. We find that alignments for several long non-coding RNAs previously shown to lack covariation support do have adequate covariation detection power, providing additional evidence against their proposed conserved structures. Availability and implementation The R-scape web server is at eddylab.org/R-scape, with a link to download the source code. Supplementary information Supplementary data are available at Bioinformatics online.
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Sabarinathan, Radhakrishnan, Christian Anthon, Jan Gorodkin, and Stefan Seemann. "Multiple Sequence Alignments Enhance Boundary Definition of RNA Structures." Genes 9, no. 12 (December 4, 2018): 604. http://dx.doi.org/10.3390/genes9120604.
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Self-contained structured domains of RNA sequences have often distinct molecular functions. Determining the boundaries of structured domains of a non-coding RNA (ncRNA) is needed for many ncRNA gene finder programs that predict RNA secondary structures in aligned genomes because these methods do not necessarily provide precise information about the boundaries or the location of the RNA structure inside the predicted ncRNA. Even without having a structure prediction, it is of interest to search for structured domains, such as for finding common RNA motifs in RNA-protein binding assays. The precise definition of the boundaries are essential for downstream analyses such as RNA structure modelling, e.g., through covariance models, and RNA structure clustering for the search of common motifs. Such efforts have so far been focused on single sequences, thus here we present a comparison for boundary definition between single sequence and multiple sequence alignments. We also present a novel approach, named RNAbound, for finding the boundaries that are based on probabilities of evolutionarily conserved base pairings. We tested the performance of two different methods on a limited number of Rfam families using the annotated structured RNA regions in the human genome and their multiple sequence alignments created from 14 species. The results show that multiple sequence alignments improve the boundary prediction for branched structures compared to single sequences independent of the chosen method. The actual performance of the two methods differs on single hairpin structures and branched structures. For the RNA families with branched structures, including transfer RNA (tRNA) and small nucleolar RNAs (snoRNAs), RNAbound improves the boundary predictions using multiple sequence alignments to median differences of −6 and −11.5 nucleotides (nts) for left and right boundary, respectively (window size of 200 nts).
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SATO, KENGO, MICHIAKI HAMADA, TOUTAI MITUYAMA, KIYOSHI ASAI, and YASUBUMI SAKAKIBARA. "A NON-PARAMETRIC BAYESIAN APPROACH FOR PREDICTING RNA SECONDARY STRUCTURES." Journal of Bioinformatics and Computational Biology 08, no. 04 (August 2010): 727–42. http://dx.doi.org/10.1142/s0219720010004926.
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Since many functional RNAs form stable secondary structures which are related to their functions, RNA secondary structure prediction is a crucial problem in bioinformatics. We propose a novel model for generating RNA secondary structures based on a non-parametric Bayesian approach, called hierarchical Dirichlet processes for stochastic context-free grammars (HDP-SCFGs). Here non-parametric means that some meta-parameters, such as the number of non-terminal symbols and production rules, do not have to be fixed. Instead their distributions are inferred in order to be adapted (in the Bayesian sense) to the training sequences provided. The results of our RNA secondary structure predictions show that HDP-SCFGs are more accurate than the MFE-based and other generative models.
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Soulé, Antoine, Vladimir Reinharz, Roman Sarrazin-Gendron, Alain Denise, and Jérôme Waldispühl. "Finding recurrent RNA structural networks with fast maximal common subgraphs of edge-colored graphs." PLOS Computational Biology 17, no. 5 (May 28, 2021): e1008990. http://dx.doi.org/10.1371/journal.pcbi.1008990.
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RNA tertiary structure is crucial to its many non-coding molecular functions. RNA architecture is shaped by its secondary structure composed of stems, stacked canonical base pairs, enclosing loops. While stems are precisely captured by free-energy models, loops composed of non-canonical base pairs are not. Nor are distant interactions linking together those secondary structure elements (SSEs). Databases of conserved 3D geometries (a.k.a. modules) not captured by energetic models are leveraged for structure prediction and design, but the computational complexity has limited their study to local elements, loops. Representing the RNA structure as a graph has recently allowed to expend this work to pairs of SSEs, uncovering a hierarchical organization of these 3D modules, at great computational cost. Systematically capturing recurrent patterns on a large scale is a main challenge in the study of RNA structures. In this paper, we present an efficient algorithm to compute maximal isomorphisms in edge colored graphs. We extend this algorithm to a framework well suited to identify RNA modules, and fast enough to considerably generalize previous approaches. To exhibit the versatility of our framework, we first reproduce results identifying all common modules spanning more than 2 SSEs, in a few hours instead of weeks. The efficiency of our new algorithm is demonstrated by computing the maximal modules between any pair of entire RNA in the non-redundant corpus of known RNA 3D structures. We observe that the biggest modules our method uncovers compose large shared sub-structure spanning hundreds of nucleotides and base pairs between the ribosomes of Thermus thermophilus, Escherichia Coli, and Pseudomonas aeruginosa.
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Ruszkowska, Agnieszka. "METTL16, Methyltransferase-Like Protein 16: Current Insights into Structure and Function." International Journal of Molecular Sciences 22, no. 4 (February 22, 2021): 2176. http://dx.doi.org/10.3390/ijms22042176.
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Methyltransferase-like protein 16 (METTL16) is a human RNA methyltransferase that installs m6A marks on U6 small nuclear RNA (U6 snRNA) and S-adenosylmethionine (SAM) synthetase pre-mRNA. METTL16 also controls a significant portion of m6A epitranscriptome by regulating SAM homeostasis. Multiple molecular structures of the N-terminal methyltransferase domain of METTL16, including apo forms and complexes with S-adenosylhomocysteine (SAH) or RNA, provided the structural basis of METTL16 interaction with the coenzyme and substrates, as well as indicated autoinhibitory mechanism of the enzyme activity regulation. Very recent structural and functional studies of vertebrate-conserved regions (VCRs) indicated their crucial role in the interaction with U6 snRNA. METTL16 remains an object of intense studies, as it has been associated with numerous RNA classes, including mRNA, non-coding RNA, long non-coding RNA (lncRNA), and rRNA. Moreover, the interaction between METTL16 and oncogenic lncRNA MALAT1 indicates the existence of METTL16 features specifically recognizing RNA triple helices. Overall, the number of known human m6A methyltransferases has grown from one to five during the last five years. METTL16, CAPAM, and two rRNA methyltransferases, METTL5/TRMT112 and ZCCHC4, have joined the well-known METTL3/METTL14. This work summarizes current knowledge about METTL16 in the landscape of human m6A RNA methyltransferases.
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Parikesit, Arli Aditya, Didik Huswo Utomo, and Nihayatul Karimah. "Determination of secondary and tertiary structures of cervical cancer lncRNA diagnostic and siRNA therapeutic biomarkers." Indonesian Journal of Biotechnology 23, no. 1 (June 11, 2018): 1. http://dx.doi.org/10.22146/ijbiotech.28508.
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Cervical cancer is one of the primary causes of mortality in women due to human papilloma virus (HPV) infection. The fingerprint of an HPV infection could be detected using a long non-coding RNA (lncRNA) biomarker, enabling it to be utilized in molecular diagnostics. The primary structure or sequences of RNA should be annotated within conventional bioinformatics tools. Therefore, this study aimed to determine the fine-grained 2D and 3D structures of lncRNA PVT1 and its respective siRNA inhibitors. lncRNA PVT1 sequences from Homo sapiens, Mus musculus, and Rattus norvegicus were retrieved from Genbank (NCBI). Prediction of the 2D structure and analysis of the interactions of the lncRNA and siRNA were performed using the Vienna RNA package. The 3D structure of the RNA was computed using the SimRNA and ModeRNA software programs. The results showed that lncRNA PVT1 from H. sapiens and M. musculus had a conserved region. However, the lncRNA from both H. sapiens and M. musculus showed a low conserved region, and the 2D structure could not be determined; thus, the annotation and 2D model focused only on H. sapiens. Both of their lncRNA PVT1 also had a short half-life in the cell. Based on the 3D modeling pipeline, the 3D model of lncRNA PVT1 showed the stability and possible function as molecules, while the PVT1 siRNA-lncRNA interaction analysis revealed that the molecules could bind well. Based on these findings, the structures of both lncRNA PVT1 and its siRNA have the potential to be utilized as biomarkers.
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Rao, Mingzhu. "Gene Expression Profile of RNA N1-methyladenosine methyltransferases." E3S Web of Conferences 218 (2020): 03052. http://dx.doi.org/10.1051/e3sconf/202021803052.
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N1-methyladenosine (m1A) is a kind of common and abundant methylation modification in eukaryotic mRNA and long-chain non-coding RNA. Nucleoside methyltransferase (MTase) of m1A is a diverse protein family, which is characterized by the presence of methyltransferases like domains and conserved S-adenosylmethionine (SAM) binding domains formed by the central sevenstranded beta-sheet structure. However, comprehensive analysis of the gene expression profile of such enzymes has not been performed to classify them according to evolutionary criteria and to guide the functional prediction. Here, we conducted extensive searches of databases to collect all members of previously identified m1A RNA methyltransferases. And we report bioinformatics studies on gene expression profile based on evolutionary analysis, sequence alignment, expression in tissues and cells within the family of RNA methyltransferases. Our analysis showed that the base modification behavior mediated by m1A RNA methyltransferases evolved from invertebrate, and the active sites of m1A RNA methyltransferases were highly conserved during the evolution from invertebrates to human. And m1A RNA methyltransferases have low tissue and cell specificity.
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Deschamps-Francoeur, Gabrielle, Daniel Garneau, Fabien Dupuis-Sandoval, Audrey Roy, Marie Frappier, Mathieu Catala, Sonia Couture, Mélissa Barbe-Marcoux, Sherif Abou-Elela, and Michelle S. Scott. "Identification of discrete classes of small nucleolar RNA featuring different ends and RNA binding protein dependency." Nucleic Acids Research 42, no. 15 (July 29, 2014): 10073–85. http://dx.doi.org/10.1093/nar/gku664.
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Abstract Small nucleolar RNAs (snoRNAs) are among the first discovered and most extensively studied group of small non-coding RNA. However, most studies focused on a small subset of snoRNAs that guide the modification of ribosomal RNA. In this study, we annotated the expression pattern of all box C/D snoRNAs in normal and cancer cell lines independent of their functions. The results indicate that C/D snoRNAs are expressed as two distinct forms differing in their ends with respect to boxes C and D and in their terminal stem length. Both forms are overexpressed in cancer cell lines but display a conserved end distribution. Surprisingly, the long forms are more dependent than the short forms on the expression of the core snoRNP protein NOP58, thought to be essential for C/D snoRNA production. In contrast, a subset of short forms are dependent on the splicing factor RBFOX2. Analysis of the potential secondary structure of both forms indicates that the k-turn motif required for binding of NOP58 is less stable in short forms which are thus less likely to mature into a canonical snoRNP. Taken together the data suggest that C/D snoRNAs are divided into at least two groups with distinct maturation and functional preferences.
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Goodfellow, Ian, Yasmin Chaudhry, Andrew Richardson, Janet Meredith, Jeffrey W. Almond, Wendy Barclay, and David J. Evans. "Identification of a cis-Acting Replication Element within the Poliovirus Coding Region." Journal of Virology 74, no. 10 (May 15, 2000): 4590–600. http://dx.doi.org/10.1128/jvi.74.10.4590-4600.2000.
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ABSTRACT The replication of poliovirus, a positive-stranded RNA virus, requires translation of the infecting genome followed by virus-encoded VPg and 3D polymerase-primed synthesis of a negative-stranded template. RNA sequences involved in the latter process are poorly defined. Since many sequences involved in picornavirus replication form RNA structures, we searched the genome, other than the untranslated regions, for predicted local secondary structural elements and identified a 61-nucleotide (nt) stem-loop in the region encoding the 2C protein. Covariance analysis suggested the structure was well conserved in the Enterovirus genus of the Picornaviridae. Site-directed mutagenesis, disrupting the structure without affecting the 2C product, destroyed genome viability and suggested that the structure was required in the positive sense for function. Recovery of revertant viruses suggested that integrity of the structure was critical for function, and analysis of replication demonstrated that nonviable mutants did not synthesize negative strands. Our conclusion, that this RNA secondary structure constitutes a novel polioviruscis-acting replication element (CRE), is supported by the demonstration that subgenomic replicons bearing lethal mutations in the native structure can be restored to replication competence by the addition of a second copy of the 61-nt wild-type sequence at another location within the genome. This poliovirus CRE functionally resembles an element identified in rhinovirus type 14 (K. L. McKnight and S. M. Lemon, RNA 4:1569–1584, 1998) and the cardioviruses (P. E. Lobert, N. Escriou, J. Ruelle, and T. Michiels, Proc. Natl. Acad. Sci. USA 96:11560–11565, 1999) but differs in sequence, structure, and location. The functional role and evolutionary significance of CREs in the replication of positive-sense RNA viruses is discussed.
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Biswas, Ashis Kumer, and Jean X. Gao. "PR2S2Clust: Patched RNA-seq read segments’ structure-oriented clustering." Journal of Bioinformatics and Computational Biology 14, no. 05 (October 2016): 1650027. http://dx.doi.org/10.1142/s021972001650027x.
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RNA-seq, the next generation sequencing platform, enables researchers to explore deep into the transcriptome of organisms, such as identifying functional non-coding RNAs (ncRNAs), and quantify their expressions on tissues. The functions of ncRNAs are mostly related to their secondary structures. Thus by exploring the clustering in terms of structural profiles of the corresponding read-segments would be essential and this fuels in our motivation behind this research. In this manuscript we proposed PR2S2Clust, Patched RNA-seq Read Segments’ Structure-oriented Clustering, which is an analysis platform to extract features to prepare the secondary structure profiles of the RNA-seq read segments. It provides a strategy to employ the profiles to annotate the segments into ncRNA classes using several clustering strategies. The system considers seven pairwise structural distance metrics by considering short-read mappings onto each structure, which we term as the “patched structure” while clustering the segments. In this regard, we show applications of both classical and ensemble clusterings of the partitional and hierarchical variations. Extensive real-world experiments over three publicly available RNA-seq datasets and a comparative analysis over four competitive systems confirm the effectiveness and superiority of the proposed system. The source codes and dataset of PR2S2Clust are available at the http://biomecis.uta.edu/~ashis/res/PR2S2Clust-suppl/ .
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Singh, Jaswinder, Kuldip Paliwal, Tongchuan Zhang, Jaspreet Singh, Thomas Litfin, and Yaoqi Zhou. "Improved RNA secondary structure and tertiary base-pairing prediction using evolutionary profile, mutational coupling and two-dimensional transfer learning." Bioinformatics 37, no. 17 (March 11, 2021): 2589–600. http://dx.doi.org/10.1093/bioinformatics/btab165.
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Abstract Motivation The recent discovery of numerous non-coding RNAs (long non-coding RNAs, in particular) has transformed our perception about the roles of RNAs in living organisms. Our ability to understand them, however, is hampered by our inability to solve their secondary and tertiary structures in high resolution efficiently by existing experimental techniques. Computational prediction of RNA secondary structure, on the other hand, has received much-needed improvement, recently, through deep learning of a large approximate data, followed by transfer learning with gold-standard base-pairing structures from high-resolution 3-D structures. Here, we expand this single-sequence-based learning to the use of evolutionary profiles and mutational coupling. Results The new method allows large improvement not only in canonical base-pairs (RNA secondary structures) but more so in base-pairing associated with tertiary interactions such as pseudoknots, non-canonical and lone base-pairs. In particular, it is highly accurate for those RNAs of more than 1000 homologous sequences by achieving >0.8 F1-score (harmonic mean of sensitivity and precision) for 14/16 RNAs tested. The method can also significantly improve base-pairing prediction by incorporating artificial but functional homologous sequences generated from deep mutational scanning without any modification. The fully automatic method (publicly available as server and standalone software) should provide the scientific community a new powerful tool to capture not only the secondary structure but also tertiary base-pairing information for building three-dimensional models. It also highlights the future of accurately solving the base-pairing structure by using a large number of natural and/or artificial homologous sequences. Availability and implementation Standalone-version of SPOT-RNA2 is available at https://github.com/jaswindersingh2/SPOT-RNA2. Direct prediction can also be made at https://sparks-lab.org/server/spot-rna2/. The datasets used in this research can also be downloaded from the GITHUB and the webserver mentioned above. Supplementary information Supplementary data are available at Bioinformatics online.
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Bentley, Kirsten, Jonathan P. Cook, Andrew K. Tuplin, and David J. Evans. "Structural and functional analysis of the roles of the HCV 5′ NCR miR122-dependent long-range association and SLVI in genome translation and replication." PeerJ 6 (November 6, 2018): e5870. http://dx.doi.org/10.7717/peerj.5870.
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The hepatitis C virus RNA genome possesses a variety of conserved structural elements, in both coding and non-coding regions, that are important for viral replication. These elements are known or predicted to modulate key life cycle events, such as translation and genome replication, some involving conformational changes induced by long-range RNA–RNA interactions. One such element is SLVI, a stem-loop (SL) structure located towards the 5′ end of the core protein-coding region. This element forms an alternative RNA–RNA interaction with complementary sequences in the 5′ untranslated regions that are independently involved in the binding of the cellular microRNA 122 (miR122). The switch between ‘open’ and ‘closed’ structures involving SLVI has previously been proposed to modulate translation, with lower translation efficiency associated with the ‘closed’ conformation. In the current study, we have used selective 2′-hydroxyl acylation analysed by primer extension to validate this RNA–RNA interaction in the absence and presence of miR122. We show that the long-range association (LRA) only forms in the absence of miR122, or otherwise requires the blocking of miR122 binding combined with substantial disruption of SLVI. Using site-directed mutations introduced to promote open or closed conformations of the LRA we demonstrate no correlation between the conformation and the translation phenotype. In addition, we observed no influence on virus replication compared to unmodified genomes. The presence of SLVI is well-documented to suppress translation, but these studies demonstrate that this is not due to its contribution to the LRA. We conclude that, although there are roles for SLVI in translation, the LRA is not a riboswitch regulating the translation and replication phenotypes of the virus.
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Heraud-Farlow, Jacki E., and Carl R. Walkley. "What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs." Open Biology 10, no. 7 (July 2020): 200085. http://dx.doi.org/10.1098/rsob.200085.
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Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA which changes its sequence, coding potential and secondary structure. Catalysed by the adenosine deaminase acting on RNA (ADAR) proteins, ADAR1 and ADAR2, A-to-I editing occurs at approximately 50 000–150 000 sites in mice and into the millions of sites in humans. The vast majority of A-to-I editing occurs in repetitive elements, accounting for the discrepancy in total numbers of sites between species. The species-conserved primary role of editing by ADAR1 in mammals is to suppress innate immune activation by unedited cell-derived endogenous RNA. In the absence of editing, inverted paired sequences, such as Alu elements, are thought to form stable double-stranded RNA (dsRNA) structures which trigger activation of dsRNA sensors, such as MDA5. A small subset of editing sites are within coding sequences and are evolutionarily conserved across metazoans. Editing by ADAR2 has been demonstrated to be physiologically important for recoding of neurotransmitter receptors in the brain. Furthermore, changes in RNA editing are associated with various pathological states, from the severe autoimmune disease Aicardi-Goutières syndrome, to various neurodevelopmental and psychiatric conditions and cancer. However, does detection of an editing site imply functional importance? Genetic studies in humans and genetically modified mouse models together with evolutionary genomics have begun to clarify the roles of A-to-I editing in vivo . Furthermore, recent developments suggest there may be the potential for distinct functions of editing during pathological conditions such as cancer.
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Fang, Chengli, Lingting Li, Liqiang Shen, Jing Shi, Sheng Wang, Yu Feng, and Yu Zhang. "Structures and mechanism of transcription initiation by bacterial ECF factors." Nucleic Acids Research 47, no. 13 (May 27, 2019): 7094–104. http://dx.doi.org/10.1093/nar/gkz470.
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Abstract Bacterial RNA polymerase (RNAP) forms distinct holoenzymes with extra-cytoplasmic function (ECF) σ factors to initiate specific gene expression programs. In this study, we report a cryo-EM structure at 4.0 Å of Escherichia coli transcription initiation complex comprising σE—the most-studied bacterial ECF σ factor (Ec σE-RPo), and a crystal structure at 3.1 Å of Mycobacterium tuberculosis transcription initiation complex with a chimeric σH/E (Mtb σH/E-RPo). The structure of Ec σE-RPo reveals key interactions essential for assembly of E. coli σE-RNAP holoenzyme and for promoter recognition and unwinding by E. coli σE. Moreover, both structures show that the non-conserved linkers (σ2/σ4 linker) of the two ECF σ factors are inserted into the active-center cleft and exit through the RNA-exit channel. We performed secondary-structure prediction of 27,670 ECF σ factors and find that their non-conserved linkers probably reach into and exit from RNAP active-center cleft in a similar manner. Further biochemical results suggest that such σ2/σ4 linker plays an important role in RPo formation, abortive production and promoter escape during ECF σ factors-mediated transcription initiation.
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Andrews, Ryan J., Collin A. O’Leary, and Walter N. Moss. "A survey of RNA secondary structural propensity encoded within human herpesvirus genomes: global comparisons and local motifs." PeerJ 8 (September 10, 2020): e9882. http://dx.doi.org/10.7717/peerj.9882.
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There are nine herpesviruses known to infect humans, of which Epstein–Barr virus (EBV) is the most widely distributed (>90% of adults infected). This ubiquitous virus is implicated in a variety of cancers and autoimmune diseases. Previous analyses of the EBV genome revealed numerous regions with evidence of generating unusually stable and conserved RNA secondary structures and led to the discovery of a novel class of EBV non-coding (nc)RNAs: the stable intronic sequence (sis)RNAs. To gain a better understanding of the roles of RNA structure in EBV biology and pathogenicity, we revisit EBV using recently developed tools for genome-wide motif discovery and RNA structural characterization. This corroborated previous results and revealed novel motifs with potential functionality; one of which has been experimentally validated. Additionally, since many herpesviruses increasingly rival the seroprevalence of EBV (VZV, HHV-6 and HHV-7 being the most notable), analyses were expanded to include all sequenced human Herpesvirus RefSeq genomes, allowing for genomic comparisons. In total 10 genomes were analyzed, for EBV (types 1 and 2), HCMV, HHV-6A, HHV-6B, HHV-7, HSV-1, HSV-2, KSHV, and VZV. All resulting data were archived in the RNAStructuromeDB (https://structurome.bb.iastate.edu/herpesvirus) to make them available to a wide array of researchers.
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Ohyama, Takako, Hazuki Takahashi, Harshita Sharma, Toshio Yamazaki, Stefano Gustincich, Yoshitaka Ishii, and Piero Carninci. "An NMR-based approach reveals the core structure of the functional domain of SINEUP lncRNAs." Nucleic Acids Research 48, no. 16 (July 22, 2020): 9346–60. http://dx.doi.org/10.1093/nar/gkaa598.
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Abstract Long non-coding RNAs (lncRNAs) are attracting widespread attention for their emerging regulatory, transcriptional, epigenetic, structural and various other functions. Comprehensive transcriptome analysis has revealed that retrotransposon elements (REs) are transcribed and enriched in lncRNA sequences. However, the functions of lncRNAs and the molecular roles of the embedded REs are largely unknown. The secondary and tertiary structures of lncRNAs and their embedded REs are likely to have essential functional roles, but experimental determination and reliable computational prediction of large RNA structures have been extremely challenging. We report here the nuclear magnetic resonance (NMR)-based secondary structure determination of the 167-nt inverted short interspersed nuclear element (SINE) B2, which is embedded in antisense Uchl1 lncRNA and upregulates the translation of sense Uchl1 mRNAs. By using NMR ‘fingerprints’ as a sensitive probe in the domain survey, we successfully divided the full-length inverted SINE B2 into minimal units made of two discrete structured domains and one dynamic domain without altering their original structures after careful boundary adjustments. This approach allowed us to identify a structured domain in nucleotides 31–119 of the inverted SINE B2. This approach will be applicable to determining the structures of other regulatory lncRNAs.
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Góra-Sochacka, Anna. "Viroids: unusual small pathogenic RNAs." Acta Biochimica Polonica 51, no. 3 (September 30, 2004): 587–607. http://dx.doi.org/10.18388/abp.2004_3546.
Full textAbstract:
Viroids are small (about 300 nucleotides), single-stranded, circular, non-encapsidated pathogenic RNA molecules. They do not code for proteins and thus depend on plant host enzymes for their replication and other functions. They induce plant diseases by direct interaction with host factors but the mechanism of pathogenicity is still unknown. They can alter the expression of selected plant genes important for growth and development. Viroids belong to two families, the Avsunviroidae and the Pospiviroidae. Viroids of the Avsunviroidae family adopt a branched or quasi rod-like secondary structure in their native state. Members of the Pospiviroidae family adopt a rod-like secondary structure. In such native structures five structural/functional domains have been identified: central (C), pathogenicity, variable and two terminal domains. The central conserved region (CCR) within the C domain characterizes viroids of the Pospiviroidae. Specific secondary structures of this region play an important role in viroid replication and processing. Viroids of the Avsunviroidae family lack a CCR but possess self-cleaving properties by forming hammerhead ribozyme structures; they accumulate and replicate in chloroplasts, whereas members of the Pospiviroidae family have a nuclear localization. Viroid replication occurs via a rolling circle mechanism using either a symmetric or asymmetric pathway in three steps, RNA transcription, processing and ligation.
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Kalendar, Ruslan, Olga Raskina, Alexander Belyayev, and Alan H. Schulman. "Long Tandem Arrays of Cassandra Retroelements and Their Role in Genome Dynamics in Plants." International Journal of Molecular Sciences 21, no. 8 (April 22, 2020): 2931. http://dx.doi.org/10.3390/ijms21082931.
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Retrotransposable elements are widely distributed and diverse in eukaryotes. Their copy number increases through reverse-transcription-mediated propagation, while they can be lost through recombinational processes, generating genomic rearrangements. We previously identified extensive structurally uniform retrotransposon groups in which no member contains the gag, pol, or env internal domains. Because of the lack of protein-coding capacity, these groups are non-autonomous in replication, even if transcriptionally active. The Cassandra element belongs to the non-autonomous group called terminal-repeat retrotransposons in miniature (TRIM). It carries 5S RNA sequences with conserved RNA polymerase (pol) III promoters and terminators in its long terminal repeats (LTRs). Here, we identified multiple extended tandem arrays of Cassandra retrotransposons within different plant species, including ferns. At least 12 copies of repeated LTRs (as the tandem unit) and internal domain (as a spacer), giving a pattern that resembles the cellular 5S rRNA genes, were identified. A cytogenetic analysis revealed the specific chromosomal pattern of the Cassandra retrotransposon with prominent clustering at and around 5S rDNA loci. The secondary structure of the Cassandra retroelement RNA is predicted to form super-loops, in which the two LTRs are complementary to each other and can initiate local recombination, leading to the tandem arrays of Cassandra elements. The array structures are conserved for Cassandra retroelements of different species. We speculate that recombination events similar to those of 5S rRNA genes may explain the wide variation in Cassandra copy number. Likewise, the organization of 5S rRNA gene sequences is very variable in flowering plants; part of what is taken for 5S gene copy variation may be variation in Cassandra number. The role of the Cassandra 5S sequences remains to be established.
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Wang, Xinying, Marli Vlok, Stephane Flibotte, and Eric Jan. "Resurrection of a Viral Internal Ribosome Entry Site from a 700 Year Old Ancient Northwest Territories Cripavirus." Viruses 13, no. 3 (March 17, 2021): 493. http://dx.doi.org/10.3390/v13030493.
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The dicistrovirus intergenic region internal ribosome entry site (IGR IRES) uses an unprecedented, streamlined mechanism whereby the IRES adopts a triple-pseudoknot (PK) structure to directly bind to the conserved core of the ribosome and drive translation from a non-AUG codon. The origin of this IRES mechanism is not known. Previously, a partial fragment of a divergent dicistrovirus RNA genome, named ancient Northwest territories cripavirus (aNCV), was extracted from 700-year-old caribou feces trapped in a subarctic ice patch. The aNCV IGR sequence adopts a secondary structure similar to contemporary IGR IRES structures, however, there are subtle differences including 105 nucleotides upstream of the IRES of unknown function. Using filter binding assays, we showed that the aNCV IRES could bind to purified ribosomes, and toeprinting analysis pinpointed the start site at a GCU alanine codon adjacent to PKI. Using a bicistronic reporter RNA, the aNCV IGR can direct translation in vitro in a PKI-dependent manner. Lastly, a chimeric infectious clone swapping in the aNCV IRES supported translation and virus infection. The characterization and resurrection of a functional IGR IRES from a divergent 700-year-old virus provides a historical framework for the importance of this viral translational mechanism.
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Kohl, Alain, Ewan F. Dunn, Anice C. Lowen, and Richard M. Elliott. "Complementarity, sequence and structural elements within the 3′ and 5′ non-coding regions of the Bunyamwera orthobunyavirus S segment determine promoter strength." Journal of General Virology 85, no. 11 (November 1, 2004): 3269–78. http://dx.doi.org/10.1099/vir.0.80407-0.
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The genome of Bunyamwera virus (BUN; family Bunyaviridae) consists of three segments of negative-sense, single-stranded RNA that are called L (large), M (medium) and S (small), according to their size. The genomic RNAs are encapsidated by the viral nucleocapsid protein to form ribonucleoprotein complexes (RNPs). The terminal 3′ and 5′ non-coding sequences are complementary and interact to give a panhandle-like structure to the RNP. Located within these non-coding sequences are elements that control replication and transcription. The sequences of the terminal 11 nt are conserved among the genome segments and are followed by shorter, complementary nucleotide motifs that are conserved on a segment-specific basis. Here, a detailed analysis of the 3′ and 5′ non-coding regions of the BUN S segment is presented. By using a mini-replicon system, it was shown that a functional BUN S promoter requires complementarity, as well as defined sequences, within the terminal 15 nt of either end. It was also shown that the minimal requirement for transcription is localized within the terminal 32 nt of the S segment. A comparison of known strong BUN promoters led to the prediction of a structural element outside the terminal 15 nt; introduction of this motif into the BUN S sequence resulted in increased antigenome and mRNA levels and increased expression of S segment proteins, as shown by mini-replicon assays, as well as recovery of a recombinant virus.
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Pang, Junling, Xia Zhang, Xuhui Ma, and Jun Zhao. "Spatio-Temporal Transcriptional Dynamics of Maize Long Non-Coding RNAs Responsive to Drought Stress." Genes 10, no. 2 (February 13, 2019): 138. http://dx.doi.org/10.3390/genes10020138.
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Long non-coding RNAs (lncRNAs) have emerged as important regulators in plant stress response. Here, we report a genome-wide lncRNA transcriptional analysis in response to drought stress using an expanded series of maize samples collected from three distinct tissues spanning four developmental stages. In total, 3488 high-confidence lncRNAs were identified, among which 1535 were characterized as drought responsive. By characterizing the genomic structure and expression pattern, we found that lncRNA structures were less complex than protein-coding genes, showing shorter transcripts and fewer exons. Moreover, drought-responsive lncRNAs exhibited higher tissue- and development-specificity than protein-coding genes. By exploring the temporal expression patterns of drought-responsive lncRNAs at different developmental stages, we discovered that the reproductive stage R1 was the most sensitive growth stage with more lncRNAs showing altered expression upon drought stress. Furthermore, lncRNA target prediction revealed 653 potential lncRNA-messenger RNA (mRNA) pairs, among which 124 pairs function in cis-acting mode and 529 in trans. Functional enrichment analysis showed that the targets were significantly enriched in molecular functions related to oxidoreductase activity, water binding, and electron carrier activity. Multiple promising targets of drought-responsive lncRNAs were discovered, including the V-ATPase encoding gene, vpp4. These findings extend our knowledge of lncRNAs as important regulators in maize drought response.
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Thompson, Jeremy R., Emanuele Buratti, Mélissanne de Wispelaere, and Mark Tepfer. "Structural and functional characterization of the 5′ region of subgenomic RNA5 of cucumber mosaic virus." Journal of General Virology 89, no. 7 (July 1, 2008): 1729–38. http://dx.doi.org/10.1099/vir.0.2008/001057-0.
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The uncapped and ORF-less subgenomic RNA5 is produced in subgroup II strains of cucumber mosaic virus (CMV), but not in subgroup I strains. Its initiation nucleotide (nt 1903) is in a 21 nt conserved sequence (Box1) that is absent in CMV subgroup I. Putative non-coding RNA structural elements surrounding Box1 in the plus and minus strand were identified in silico and by in vitro RNase probing. Four main stem–loop structures (SLM, SLL, SLK and SLJ) were identified between nt 1887 and 1999 of isolate R-CMV (subgroup II), with notable differences within SLM and SLL between the two strands. Mutation of a stem–loop within SLM, even when the predicted wild-type structure was maintained, showed significant reduction in RNA5 levels in planta. Three mutants containing 3–4 nt substitutions between positions −39 and +49 showed significantly reduced levels of RNA5, while another similar mutant at positions 80–83 had RNA5 levels comparable to wild-type. Deletion of Box1 resulted in similar levels of RNA3 and 4 as wild-type, while eliminating RNA5. Insertion of Box1 into a subgroup I isolate was not sufficient to produce RNA5. However, in a mutant with an additional 21 nt of R-CMV 3′ of Box1 (positions −1 to +41), low levels of RNA5 were detected. Taken together, these results have identified regions of the viral genome responsible for RNA5 production and in addition provide strong evidence for the existence of newly identified conserved structural elements in the 5′ part of the 3′ untranslated region.
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Wen, Jing, Peng-Feng Li, Feng Ran, Peng-Cheng Guo, Jia-Tian Zhu, Jin Yang, Lan-Lan Zhang, Ping Chen, Jia-Na Li, and Hai Du. "Genome-wide characterization, expression analyses, and functional prediction of the NPF family in Brassica napus." BMC Genomics 21, no. 1 (December 2020). http://dx.doi.org/10.1186/s12864-020-07274-7.
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Abstract Background NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NRT1/PTR) family (NPF) members are essential transporters for many substrates in plants, including nitrate, hormones, peptides, and secondary metabolites. Here, we report the global characterization of NPF in the important oil crop Brassica napus, including that for phylogeny, gene/protein structures, duplications, and expression patterns. Results A total of 199 B. napus (BnaNPFs) NPF-coding genes were identified. Phylogenetic analyses categorized these genes into 11 subfamilies, including three new ones. Sequence feature analysis revealed that members of each subfamily contain conserved gene and protein structures. Many hormone−/abiotic stress-responsive cis-acting elements and transcription factor binding sites were identified in BnaNPF promoter regions. Chromosome distribution analysis indicated that BnaNPFs within a subfamily tend to cluster on one chromosome. Syntenic relationship analysis showed that allotetraploid creation by its ancestors (Brassica rapa and Brassica oleracea) (57.89%) and small-scale duplication events (39.85%) contributed to rapid BnaNPF expansion in B. napus. A genome-wide spatiotemporal expression survey showed that NPF genes of each Arabidopsis and B. napus subfamily have preferential expression patterns across developmental stages, most of them are expressed in a few organs. RNA-seq analysis showed that many BnaNPFs (32.66%) have wide exogenous hormone-inductive profiles, suggesting important hormone-mediated patterns in diverse bioprocesses. Homologs in a clade or branch within a given subfamily have conserved organ/spatiotemporal and hormone-inductive profiles, indicating functional conservation during evolution. qRT-PCR-based comparative expression analysis of the 12 BnaNPFs in the NPF2–1 subfamily between high- and low-glucosinolate (GLS) content B. napus varieties revealed that homologs of AtNPF2.9 (BnaNPF2.12, BnaNPF2.13, and BnaNPF2.14), AtNPF2.10 (BnaNPF2.19 and BnaNPF2.20), and AtNPF2.11 (BnaNPF2.26 and BnaNPF2.28) might be involved in GLS transport. qRT-PCR further confirmed the hormone-responsive expression profiles of these putative GLS transporter genes. Conclusion We identified 199 B. napus BnaNPFs; these were divided into 11 subfamilies. Allopolyploidy and small-scale duplication events contributed to the immense expansion of BnaNPFs in B. napus. The BnaNPFs had preferential expression patterns in different tissues/organs and wide hormone-induced expression profiles. Four BnaNPFs in the NPF2–1 subfamily may be involved in GLS transport. Our results provide an abundant gene resource for further functional analysis of BnaNPFs.
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Gultyaev, Alexander P., Mathilde Richard, Monique I. Spronken, René C. L. Olsthoorn, and Ron A. M. Fouchier. "Conserved structural RNA domains in regions coding for cleavage site motifs in hemagglutinin genes of influenza viruses." Virus Evolution 5, no. 2 (July 1, 2019). http://dx.doi.org/10.1093/ve/vez034.
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Abstract The acquisition of a multibasic cleavage site (MBCS) in the hemagglutinin (HA) glycoprotein is the main determinant of the conversion of low pathogenic avian influenza viruses into highly pathogenic strains, facilitating HA cleavage and virus replication in a broader range of host cells. In nature, substitutions or insertions in HA RNA genomic segments that code for multiple basic amino acids have been observed only in the HA genes of two out of sixteen subtypes circulating in birds, H5 and H7. Given the compatibility of MBCS motifs with HA proteins of numerous subtypes, this selectivity was hypothesized to be determined by the existence of specific motifs in HA RNA, in particular structured domains. In H5 and H7 HA RNAs, predictions of such domains have yielded alternative conserved stem-loop structures with the cleavage site codons in the hairpin loops. Here, potential RNA secondary structures were analyzed in the cleavage site regions of HA segments of influenza viruses of different types and subtypes. H5- and H7-like stem-loop structures were found in all known influenza A virus subtypes and in influenza B and C viruses with homology modeling. Nucleotide covariations supported this conservation to be determined by RNA structural constraints that are stronger in the domain-closing bottom stems as compared to apical parts. The structured character of this region in (sub-)types other than H5 and H7 indicates its functional importance beyond the ability to evolve toward an MBCS responsible for a highly pathogenic phenotype.
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Sato, Kengo, Manato Akiyama, and Yasubumi Sakakibara. "RNA secondary structure prediction using deep learning with thermodynamic integration." Nature Communications 12, no. 1 (February 11, 2021). http://dx.doi.org/10.1038/s41467-021-21194-4.
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AbstractAccurate predictions of RNA secondary structures can help uncover the roles of functional non-coding RNAs. Although machine learning-based models have achieved high performance in terms of prediction accuracy, overfitting is a common risk for such highly parameterized models. Here we show that overfitting can be minimized when RNA folding scores learnt using a deep neural network are integrated together with Turner’s nearest-neighbor free energy parameters. Training the model with thermodynamic regularization ensures that folding scores and the calculated free energy are as close as possible. In computational experiments designed for newly discovered non-coding RNAs, our algorithm (MXfold2) achieves the most robust and accurate predictions of RNA secondary structures without sacrificing computational efficiency compared to several other algorithms. The results suggest that integrating thermodynamic information could help improve the robustness of deep learning-based predictions of RNA secondary structure.
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Cheng, Clarence Yu, Fang-Chieh Chou, Wipapat Kladwang, Siqi Tian, Pablo Cordero, and Rhiju Das. "Consistent global structures of complex RNA states through multidimensional chemical mapping." eLife 4 (June 2, 2015). http://dx.doi.org/10.7554/elife.07600.
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Accelerating discoveries of non-coding RNA (ncRNA) in myriad biological processes pose major challenges to structural and functional analysis. Despite progress in secondary structure modeling, high-throughput methods have generally failed to determine ncRNA tertiary structures, even at the 1-nm resolution that enables visualization of how helices and functional motifs are positioned in three dimensions. We report that integrating a new method called MOHCA-seq (Multiplexed •OH Cleavage Analysis with paired-end sequencing) with mutate-and-map secondary structure inference guides Rosetta 3D modeling to consistent 1-nm accuracy for intricately folded ncRNAs with lengths up to 188 nucleotides, including a blind RNA-puzzle challenge, the lariat-capping ribozyme. This multidimensional chemical mapping (MCM) pipeline resolves unexpected tertiary proximities for cyclic-di-GMP, glycine, and adenosylcobalamin riboswitch aptamers without their ligands and a loose structure for the recently discovered human HoxA9D internal ribosome entry site regulon. MCM offers a sequencing-based route to uncovering ncRNA 3D structure, applicable to functionally important but potentially heterogeneous states.
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Zhou, Ting, Huiwen Wang, Chen Zeng, and Yunjie Zhao. "RPocket: an intuitive database of RNA pocket topology information with RNA-ligand data resources." BMC Bioinformatics 22, no. 1 (September 8, 2021). http://dx.doi.org/10.1186/s12859-021-04349-4.
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Abstract Background RNA regulates a variety of biological functions by interacting with other molecules. The ligand often binds in the RNA pocket to trigger structural changes or functions. Thus, it is essential to explore and visualize the RNA pocket to elucidate the structural and recognition mechanism for the RNA-ligand complex formation. Results In this work, we developed one user-friendly bioinformatics tool, RPocket. This database provides geometrical size, centroid, shape, secondary structure element for RNA pocket, RNA-ligand interaction information, and functional sites. We extracted 240 RNA pockets from 94 non-redundant RNA-ligand complex structures. We developed RPDescriptor to calculate the pocket geometrical property quantitatively. The geometrical information was then subjected to RNA-ligand binding analysis by incorporating the sequence, secondary structure, and geometrical combinations. This new approach takes advantage of both the atom-level precision of the structure and the nucleotide-level tertiary interactions. The results show that the higher-level topological pattern indeed improves the tertiary structure prediction. We also proposed a potential mechanism for RNA-ligand complex formation. The electrostatic interactions are responsible for long-range recognition, while the Van der Waals and hydrophobic contacts for short-range binding and optimization. These interaction pairs can be considered as distance constraints to guide complex structural modeling and drug design. Conclusion RPocket database would facilitate RNA-ligand engineering to regulate the complex formation for biological or medical applications. RPocket is available at http://zhaoserver.com.cn/RPocket/RPocket.html.
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Zhou, Guangyao, Jackson Loper, and Stuart Geman. "Base-pair ambiguity and the kinetics of RNA folding." BMC Bioinformatics 20, no. 1 (December 2019). http://dx.doi.org/10.1186/s12859-019-3303-6.
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Abstract Background A folding RNA molecule encounters multiple opportunities to form non-native yet energetically favorable pairings of nucleotide sequences. Given this forbidding free-energy landscape, mechanisms have evolved that contribute to a directed and efficient folding process, including catalytic proteins and error-detecting chaperones. Among structural RNA molecules we make a distinction between “bound” molecules, which are active as part of ribonucleoprotein (RNP) complexes, and “unbound,” with physiological functions performed without necessarily being bound in RNP complexes. We hypothesized that unbound molecules, lacking the partnering structure of a protein, would be more vulnerable than bound molecules to kinetic traps that compete with native stem structures. We defined an “ambiguity index”—a normalized function of the primary and secondary structure of an individual molecule that measures the number of kinetic traps available to nucleotide sequences that are paired in the native structure, presuming that unbound molecules would have lower indexes. The ambiguity index depends on the purported secondary structure, and was computed under both the comparative (“gold standard”) and an equilibrium-based prediction which approximates the minimum free energy (MFE) structure. Arguing that kinetically accessible metastable structures might be more biologically relevant than thermodynamic equilibrium structures, we also hypothesized that MFE-derived ambiguities would be less effective in separating bound and unbound molecules. Results We have introduced an intuitive and easily computed function of primary and secondary structures that measures the availability of complementary sequences that could disrupt the formation of native stems on a given molecule—an ambiguity index. Using comparative secondary structures, the ambiguity index is systematically smaller among unbound than bound molecules, as expected. Furthermore, the effect is lost when the presumably more accurate comparative structure is replaced instead by the MFE structure. Conclusions A statistical analysis of the relationship between the primary and secondary structures of non-coding RNA molecules suggests that stem-disrupting kinetic traps are substantially less prevalent in molecules not participating in RNP complexes. In that this distinction is apparent under the comparative but not the MFE secondary structure, the results highlight a possible deficiency in structure predictions when based upon assumptions of thermodynamic equilibrium.
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Singh, Jaswinder, Jack Hanson, Kuldip Paliwal, and Yaoqi Zhou. "RNA secondary structure prediction using an ensemble of two-dimensional deep neural networks and transfer learning." Nature Communications 10, no. 1 (November 27, 2019). http://dx.doi.org/10.1038/s41467-019-13395-9.
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AbstractThe majority of our human genome transcribes into noncoding RNAs with unknown structures and functions. Obtaining functional clues for noncoding RNAs requires accurate base-pairing or secondary-structure prediction. However, the performance of such predictions by current folding-based algorithms has been stagnated for more than a decade. Here, we propose the use of deep contextual learning for base-pair prediction including those noncanonical and non-nested (pseudoknot) base pairs stabilized by tertiary interactions. Since only $$<$$<250 nonredundant, high-resolution RNA structures are available for model training, we utilize transfer learning from a model initially trained with a recent high-quality bpRNA dataset of $$> $$>10,000 nonredundant RNAs made available through comparative analysis. The resulting method achieves large, statistically significant improvement in predicting all base pairs, noncanonical and non-nested base pairs in particular. The proposed method (SPOT-RNA), with a freely available server and standalone software, should be useful for improving RNA structure modeling, sequence alignment, and functional annotations.
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Miladi, Milad, Eteri Sokhoyan, Torsten Houwaart, Steffen Heyne, Fabrizio Costa, Björn Grüning, and Rolf Backofen. "GraphClust2: Annotation and discovery of structured RNAs with scalable and accessible integrative clustering." GigaScience 8, no. 12 (December 1, 2019). http://dx.doi.org/10.1093/gigascience/giz150.
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Abstract Background RNA plays essential roles in all known forms of life. Clustering RNA sequences with common sequence and structure is an essential step towards studying RNA function. With the advent of high-throughput sequencing techniques, experimental and genomic data are expanding to complement the predictive methods. However, the existing methods do not effectively utilize and cope with the immense amount of data becoming available. Results Hundreds of thousands of non-coding RNAs have been detected; however, their annotation is lagging behind. Here we present GraphClust2, a comprehensive approach for scalable clustering of RNAs based on sequence and structural similarities. GraphClust2 bridges the gap between high-throughput sequencing and structural RNA analysis and provides an integrative solution by incorporating diverse experimental and genomic data in an accessible manner via the Galaxy framework. GraphClust2 can efficiently cluster and annotate large datasets of RNAs and supports structure-probing data. We demonstrate that the annotation performance of clustering functional RNAs can be considerably improved. Furthermore, an off-the-shelf procedure is introduced for identifying locally conserved structure candidates in long RNAs. We suggest the presence and the sparseness of phylogenetically conserved local structures for a collection of long non-coding RNAs. Conclusions By clustering data from 2 cross-linking immunoprecipitation experiments, we demonstrate the benefits of GraphClust2 for motif discovery under the presence of biological and methodological biases. Finally, we uncover prominent targets of double-stranded RNA binding protein Roquin-1, such as BCOR’s 3′ untranslated region that contains multiple binding stem-loops that are evolutionary conserved.
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Cataldo, Pablo Gabriel, Paul Klemm, Marietta Thüring, Lucila Saavedra, Elvira Maria Hebert, Roland K. Hartmann, and Marcus Lechner. "Insights into 6S RNA in lactic acid bacteria (LAB)." BMC Genomic Data 22, no. 1 (September 3, 2021). http://dx.doi.org/10.1186/s12863-021-00983-2.
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Abstract Background 6S RNA is a regulator of cellular transcription that tunes the metabolism of cells. This small non-coding RNA is found in nearly all bacteria and among the most abundant transcripts. Lactic acid bacteria (LAB) constitute a group of microorganisms with strong biotechnological relevance, often exploited as starter cultures for industrial products through fermentation. Some strains are used as probiotics while others represent potential pathogens. Occasional reports of 6S RNA within this group already indicate striking metabolic implications. A conceivable idea is that LAB with 6S RNA defects may metabolize nutrients faster, as inferred from studies of Echerichia coli. This may accelerate fermentation processes with the potential to reduce production costs. Similarly, elevated levels of secondary metabolites might be produced. Evidence for this possibility comes from preliminary findings regarding the production of surfactin in Bacillus subtilis, which has functions similar to those of bacteriocins. The prerequisite for its potential biotechnological utility is a general characterization of 6S RNA in LAB. Results We provide a genomic annotation of 6S RNA throughout the Lactobacillales order. It laid the foundation for a bioinformatic characterization of common 6S RNA features. This covers secondary structures, synteny, phylogeny, and product RNA start sites. The canonical 6S RNA structure is formed by a central bulge flanked by helical arms and a template site for product RNA synthesis. 6S RNA exhibits strong syntenic conservation. It is usually flanked by the replication-associated recombination protein A and the universal stress protein A. A catabolite responsive element was identified in over a third of all 6S RNA genes. It is known to modulate gene expression based on the available carbon sources. The presence of antisense transcripts could not be verified as a general trait of LAB 6S RNAs. Conclusions Despite a large number of species and the heterogeneity of LAB, the stress regulator 6S RNA is well-conserved both from a structural as well as a syntenic perspective. This is the first approach to describe 6S RNAs and short 6S RNA-derived transcripts beyond a single species, spanning a large taxonomic group covering multiple families. It yields universal insights into this regulator and complements the findings derived from other bacterial model organisms.
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Clark, Daniel N., John M. Flanagan, and Jianming Hu. "Mapping of Functional Subdomains in the Terminal Protein Domain of Hepatitis B Virus Polymerase." Journal of Virology 91, no. 3 (November 16, 2016). http://dx.doi.org/10.1128/jvi.01785-16.
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ABSTRACTHepatitis B virus (HBV) encodes a multifunction reverse transcriptase or polymerase (P), which is composed of several domains. The terminal protein (TP) domain is unique to HBV and related hepadnaviruses and is required for specifically binding to the viral pregenomic RNA (pgRNA). Subsequently, the TP domain is necessary for pgRNA packaging into viral nucleocapsids and the initiation of viral reverse transcription for conversion of the pgRNA to viral DNA. Uniquely, the HBV P protein initiates reverse transcription via a protein priming mechanism using the TP domain as a primer. No structural homologs or high-resolution structure exists for the TP domain. Secondary structure prediction identified three disordered loops in TP with highly conserved sequences. A meta-analysis of mutagenesis studies indicated these predicted loops are almost exclusively where functionally important residues are located. Newly constructed TP mutations revealed a priming loop in TP which plays a specific role in protein-primed DNA synthesis beyond simply harboring the site of priming. Substitutions of potential sites of phosphorylation surrounding the priming site demonstrated that these residues are involved in interactions critical for priming but are unlikely to be phosphorylated during viral replication. Furthermore, the first 13 and 66 TP residues were shown to be dispensable for protein priming and pgRNA binding, respectively. Combining current and previous mutagenesis work with sequence analysis has increased our understanding of TP structure and functions by mapping specific functions to distinct predicted secondary structures and will facilitate antiviral targeting of this unique domain.IMPORTANCEHBV is a major cause of viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. One important feature of this virus is its polymerase, the enzyme used to create the DNA genome from a specific viral RNA by reverse transcription. One region of this polymerase, the TP domain, is required for association with the viral RNA and production of the DNA genome. Targeting the TP domain for antiviral development is difficult due to the lack of homology to other proteins and high-resolution structure. This study mapped the TP functions according to predicted secondary structure, where it folds into alpha helices or unstructured loops. Three predicted loops were found to be the most important regions functionally and the most conserved evolutionarily. Identification of these functional subdomains in TP will facilitate its targeting for antiviral development.