Pre-mRNA structures forming circular RNAs

Welden, Justin R.; Stamm, Stefan

doi:10.1016/j.bbagrm.2019.194410

Cited by 32 publications

(28 citation statements)

References 65 publications

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“…The existence of associations between long-range RNA structure and splicing has been noted in previous studies 7, including our earlier reports (27)(28)(29). The trends that were proposed for smaller sets also hold for the extended catalog of PCCRs presented here, namely the preference of PCCRs to be positioned within introns proximally to splice sites (27), lower inclusion rate of looped-out exons (33,74), circumscription of circRNAs (75), avoidance of intronic branch points (76,77), and generally obstructive effect on splice sites that are implicated in double-stranded structure (78)(79)(80). We additionally observed a remarkable overlap of PCCRs with A-to-I RNA editing sites and multiple associations with forked eCLIP peaks, which reveal traces of multi-molecular complexes with patterns that are specific to double-stranded regions.…”

Section: Discussionsupporting

confidence: 83%

“…The existence of associations between long-range RNA structure and splicing has been suggested in previous studies [7], including our earlier reports [34,33,28]. The extended catalog of PCCRs presented here demonstrates that the trends proposed for smaller sets also hold at the transcriptome-wide level, namely the preference of PCCRs to be positioned within introns proximally to splice sites [28], lower inclusion rate of looped-out exons [79,80], circumscription of circRNAs [81], avoidance of intronic branch points [82,83], and generally obstructive effect on splice sites that are implicated in double-stranded structure [84,85,86].…”

Section: Discussionsupporting

confidence: 78%

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Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Kalmykova

Kalinina

Denisov

et al. 2020

Preprint

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The ability of nucleic acids to form double-stranded structures is essential for all living systems on Earth. While DNA employs it for genome replication, RNA molecules fold into complicated secondary and tertiary structures. Current knowledge on functional RNA structures in human protein-coding genes is focused on locally-occurring base pairs. However, chemical crosslinking and proximity ligation experiments have demonstrated that long-range RNA structures are highly abundant. Here, we present the most complete to-date catalog of conserved long-range RNA structures in the human transcriptome, which consists of 1.1 million pairs of conserved complementary regions (PCCRs). PCCRs tend to occur within introns proximally to splice sites, suppress intervening exons, circumscribe circular RNAs, and exert an obstructive effect on cryptic and inactive splice sites. The double-stranded structure of PCCRs is supported by a significant decrease of icSHAPE nucleotide accessibility, high abundance of A-to-I RNA editing sites, and frequent nearby occurrence of forked eCLIP peaks. Introns with PCCRs show a distinct splicing pattern in response to RNA Pol II slowdown suggesting that splicing is widely affected by co-transcriptional RNA folding. Additionally, transcript starts and ends are strongly enriched in regions between complementary parts of PCCRs, leading to an intriguing hypothesis that RNA folding coupled with splicing could mediate co-transcriptional suppression of premature cleavage and polyadenylation events. PCCR detection procedure is highly sensitive with respect to bona fide validated RNA structures at the expense of having a high false positive rate, which cannot be reduced without loss of sensitivity.The catalog of PCCRs is visualized through a UCSC Genome Browser track hub to facilitate further genome research on long-range RNA structures.Double-stranded structure is a key feature of nucleic acids that enables replicating the genomic information and underlies fundamental cellular processes [1,2]. Many RNAs adopt functional secondary structures, and mRNAs are no exception although their main role is to encode proteins [3,4,5,6]. In eukaryotes, RNA structure affects gene expression through modulating all steps of pre-mRNA processing including splicing [7], cleavage and polyadenylation [8], and RNA editing [9]. The loss of functional RNA structure has been increasingly reported as implicated in hereditary disease and cancer [10,11,12,13].Recent progress in high-throughput sequencing techniques enabled several experimental strategies to determine RNA structure in vivo [14,15,16]. Chemical RNA structure probing can reveal which bases are single-or double-stranded, but it cannot determine which nucleotides form base pairs [17,18,19,20,21].In order to identify the interacting partners, RNA structure probing has to be combined with de novo RNA structure prediction [22], but due to a number of technical limitations such methods cannot account for base pairings that are far apart [23]. Photo-inducible RNA crosslinking a...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 78%

Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Kalmykova

Kalinina

Denisov

et al. 2020

Preprint

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“…Circular RNAs (circRNAs), an emerging class of RNA 12 , are formed through a back-splicing mechanism 13 . Back-splicing is potentiated by secondary structures in the pre-mRNAs, and these secondary structures are often generated by inverted Alu elements 14–16 .…”

Section: Resultsmentioning

confidence: 99%

Aluinsertion-mediated dsRNA structure formation with pre-existingAluelements as a novel disease-causing mechanism

Masson

Maestri

Cooper

et al. 2020

Preprint

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We have recently reported a homozygous Alu insertion variant (termed Alu_Ins) within the 3’-untranslated region (3’-UTR) of the SPINK1 gene as the cause of a new pediatric disease entity. Although Alu-Ins has been shown, by means of a full-length gene expression assay (FLGEA), to result in the complete loss of SPINK1 mRNA expression, the precise underlying mechanism(s) has remained elusive. Herein, we filled this knowledge gap by adopting a hypothesis-driven approach. Employing RepeatMasker, we identified two Alu elements (termed Alu1 and Alu2) within the SPINK1 locus; both are located deep within intron 3 and, most importantly, reside in the opposite orientation to Alu-Ins. Using FLGEA, we provide convincing evidence that Alu-Ins disrupts splicing by forming RNA secondary structures with Alu1 in the pre-mRNA sequence. Our findings reveal a previously undescribed disease-causing mechanism, resulting from an Alu insertion variant, which has implications for Alu detection and interpretation in human disease genes.

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“…In addition, tRNA is clover-shaped and can be regarded as circular in terms of topology. Pre-mRNA [25] and phytopathogenic virus viroid [26] are also circular. Although we have not found any miRNA reports that are circular, miRNA secondary structure suggests a circular shape.…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between the miRNA Sequence and Disease May be Revealed by Focusing on Hydrogen Bonding Sites in RNA–RNA Interactions

Osone

Yoshida

2019

Cells

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MicroRNAs are important genes in biological processes. Although the function of microRNAs has been elucidated, the relationship between the sequence and the disease is not sufficiently clear. It is important to clarify the relationship between the sequence and the disease because it is possible to clarify the meaning of the microRNA genetic code consisting of four nucleobases. Since seed theory is based on sequences, its development can be expected to reveal the meaning of microRNA sequences. However, this method has many false positives and false negatives. On the other hand, disease-related microRNA searches using network analysis are not based on sequences, so it is difficult to clarify the relationship between sequences and diseases. Therefore, RNA-RNA interactions which are caused by hydrogen bonding were focused on. As a result, it was clarified that sequences and diseases were highly correlated by calculating the electric field in microRNA which is considered as the torus. It was also suggested that four diseases with different major classifications can be distinguished. Conventionally, RNA was interpreted as a one-dimensional array of four nucleobases, but a new approach to RNA from this study can be expected to provide a new perspective on RNA-RNA interactions.

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Pre-mRNA structures forming circular RNAs

Cited by 32 publications

References 65 publications

Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Conserved long-range base pairings are associated with pre-mRNA processing of human genes

Aluinsertion-mediated dsRNA structure formation with pre-existingAluelements as a novel disease-causing mechanism

The Relationship Between the miRNA Sequence and Disease May be Revealed by Focusing on Hydrogen Bonding Sites in RNA–RNA Interactions

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