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Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions

RNA structure has been increasingly recognized as a critical player in the biogenesis and turnover of many transcripts classes. In eukaryotes, the prediction of RNA structure by thermodynamic modeling meets fundamental limitations due to the large sizes and complex, discontinuous organization of euk...

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Autores principales: Margasyuk, Sergey, Zavileyskiy, Lev, Cao, Changchang, Pervouchine, Dmitri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691357/
https://www.ncbi.nlm.nih.gov/pubmed/38047033
http://dx.doi.org/10.7717/peerj.16414
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author Margasyuk, Sergey
Zavileyskiy, Lev
Cao, Changchang
Pervouchine, Dmitri
author_facet Margasyuk, Sergey
Zavileyskiy, Lev
Cao, Changchang
Pervouchine, Dmitri
author_sort Margasyuk, Sergey
collection PubMed
description RNA structure has been increasingly recognized as a critical player in the biogenesis and turnover of many transcripts classes. In eukaryotes, the prediction of RNA structure by thermodynamic modeling meets fundamental limitations due to the large sizes and complex, discontinuous organization of eukaryotic genes. Signatures of functional RNA structures can be found by detecting compensatory substitutions in homologous sequences, but a comparative approach is applicable only within conserved sequence blocks. Here, we developed a computational pipeline called PHRIC, which is not limited to conserved regions and relies on RNA contacts derived from RNA in situ conformation sequencing (RIC-seq) experiments. It extracts pairs of short RNA fragments surrounded by nested clusters of RNA contacts and predicts long, nearly perfect complementary base pairings formed between these fragments. In application to a panel of RIC-seq experiments in seven human cell lines, PHRIC predicted ~12,000 stable long-range RNA structures with equilibrium free energy below −15 kcal/mol, the vast majority of which fall outside of regions annotated as conserved among vertebrates. These structures, nevertheless, show some level of sequence conservation and remarkable compensatory substitution patterns in other clades. Furthermore, we found that introns have a higher propensity to form stable long-range RNA structures between each other, and moreover that RNA structures tend to concentrate within the same intron rather than connect adjacent introns. These results for the first time extend the application of proximity ligation assays to RNA structure prediction beyond conserved regions.
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spelling pubmed-106913572023-12-02 Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions Margasyuk, Sergey Zavileyskiy, Lev Cao, Changchang Pervouchine, Dmitri PeerJ Bioinformatics RNA structure has been increasingly recognized as a critical player in the biogenesis and turnover of many transcripts classes. In eukaryotes, the prediction of RNA structure by thermodynamic modeling meets fundamental limitations due to the large sizes and complex, discontinuous organization of eukaryotic genes. Signatures of functional RNA structures can be found by detecting compensatory substitutions in homologous sequences, but a comparative approach is applicable only within conserved sequence blocks. Here, we developed a computational pipeline called PHRIC, which is not limited to conserved regions and relies on RNA contacts derived from RNA in situ conformation sequencing (RIC-seq) experiments. It extracts pairs of short RNA fragments surrounded by nested clusters of RNA contacts and predicts long, nearly perfect complementary base pairings formed between these fragments. In application to a panel of RIC-seq experiments in seven human cell lines, PHRIC predicted ~12,000 stable long-range RNA structures with equilibrium free energy below −15 kcal/mol, the vast majority of which fall outside of regions annotated as conserved among vertebrates. These structures, nevertheless, show some level of sequence conservation and remarkable compensatory substitution patterns in other clades. Furthermore, we found that introns have a higher propensity to form stable long-range RNA structures between each other, and moreover that RNA structures tend to concentrate within the same intron rather than connect adjacent introns. These results for the first time extend the application of proximity ligation assays to RNA structure prediction beyond conserved regions. PeerJ Inc. 2023-11-28 /pmc/articles/PMC10691357/ /pubmed/38047033 http://dx.doi.org/10.7717/peerj.16414 Text en © 2023 Margasyuk et al. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits using, remixing, and building upon the work non-commercially, as long as it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Bioinformatics
Margasyuk, Sergey
Zavileyskiy, Lev
Cao, Changchang
Pervouchine, Dmitri
Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions
title Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions
title_full Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions
title_fullStr Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions
title_full_unstemmed Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions
title_short Long-range RNA structures in the human transcriptome beyond evolutionarily conserved regions
title_sort long-range rna structures in the human transcriptome beyond evolutionarily conserved regions
topic Bioinformatics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691357/
https://www.ncbi.nlm.nih.gov/pubmed/38047033
http://dx.doi.org/10.7717/peerj.16414
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