Conserved long-range RNA structures associated with splicing markup and pre-mRNA processing of human genes

2020 ◽  
Author(s):  
Dmitri Pervouchine
Keyword(s):  
Long Range ◽  
Mrna Processing ◽  
Rna Structures ◽  
Human Genes

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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Svetlana Kalmykova ◽  
Marina Kalinina ◽  
Stepan Denisov ◽  
Alexey Mironov ◽  
Dmitry Skvortsov ◽  
...  
Keyword(s):  
Long Range ◽  
Rna Folding ◽  
Current Knowledge ◽  
Rna Structures ◽  
Base Pairs ◽  
Protein Coding ◽  
Proximity Ligation ◽  
Transcriptional Suppression ◽  
Human Genes ◽  
Cleavage And Polyadenylation

AbstractThe ability of nucleic acids to form double-stranded structures is essential for all living systems on Earth. Current knowledge on functional RNA structures is focused on locally-occurring base pairs. However, crosslinking and proximity ligation experiments demonstrated that long-range RNA structures are highly abundant. Here, we present the most complete to-date catalog of conserved complementary regions (PCCRs) in human protein-coding genes. PCCRs tend to occur within introns, suppress intervening exons, and obstruct cryptic and inactive splice sites. Double-stranded structure of PCCRs is supported by decreased icSHAPE nucleotide accessibility, high abundance of RNA editing sites, and frequent occurrence of forked eCLIP peaks. Introns with PCCRs show a distinct splicing pattern in response to RNAPII slowdown suggesting that splicing is widely affected by co-transcriptional RNA folding. The enrichment of 3’-ends within PCCRs raises the intriguing hypothesis that coupling between RNA folding and splicing could mediate co-transcriptional suppression of premature pre-mRNA cleavage and polyadenylation.

scholarly journals Mining for recurrent long-range interactions in RNA structures reveals embedded hierarchies in network families

2018 ◽  
Vol 46 (8) ◽  
pp. 3841-3851 ◽  
Author(s):  
Vladimir Reinharz ◽  
Antoine Soulé ◽  
Eric Westhof ◽  
Jérôme Waldispühl ◽  
Alain Denise
Keyword(s):  
Long Range ◽  
Rna Structures ◽  
Long Range Interactions

scholarly journals Modulation of alternative splicing by long-range RNA structures in Drosophila

2009 ◽  
Vol 37 (14) ◽  
pp. 4533-4544 ◽  
Author(s):  
Veronica A. Raker ◽  
Andrei A. Mironov ◽  
Mikhail S. Gelfand ◽  
Dmitri D. Pervouchine
Keyword(s):  
Alternative Splicing ◽  
Long Range ◽  
Rna Structures

scholarly journals Evidence for Widespread Association of Mammalian Splicing and Conserved Long-Range RNA Structures

2012 ◽  
pp. 199-199
Author(s):  
Dmitri Pervouchine ◽  
Ekaterina Khrameeva ◽  
Marina Pichugina ◽  
Olexii Nikolaienko ◽  
Mikhail Gelfand ◽  
...  
Keyword(s):  
Long Range ◽  
Rna Structures

scholarly journals Multiple competing RNA structures dynamically control alternative splicing in human ATE1 gene

2020 ◽  
Author(s):  
Marina Kalinina ◽  
Dmitry Skvortsov ◽  
Svetlana Kalmykova ◽  
Timofei Ivanov ◽  
Olga Dontsova ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Long Range ◽  
Rna Structure ◽  
Cancer Metastasis ◽  
Prognostic Indicator ◽  
Male Meiosis ◽  
Locked Nucleic Acid ◽  
Rna Structures ◽  
New Horizons ◽  
Prostate Cancer Metastasis

AbstractThe mammalian Ate1 gene encodes an arginyl transferase enzyme, which is essential for embryogenesis, male meiosis, and regulation of the cytoskeleton. Reduced levels of Ate1 are associated with malignant transformations and serve as a prognostic indicator of prostate cancer metastasis. The tumor suppressor function of Ate1 depends on the inclusion of one of the two mutually exclusive exons (MXE), exons 7a and 7b. Here, we report that the molecular mechanism underlying MXE splicing in Ate1 involves five conserved regulatory intronic elements R1–R5, of which R1 and R4 compete for base pairing with R3, while R2 and R5 form an ultra-long-range RNA structure spanning 30 Kb. In minigenes, single and double mutations that disrupt base pairings in R1R3 and R3R4 lead to the loss of MXE splicing, while compensatory triple mutations that restore the RNA structure also revert splicing to that of the wild type. Blocking the competing base pairings by locked nucleic acid (LNA)/DNA mixmers complementary to R3 leads to the loss of MXE splicing, while the disruption of the ultra-long-range R2R5 interaction changes the ratio of mutually exclusive isoforms in the endogenous Ate1 pre-mRNA. The upstream exon 7a becomes more included than the downstream exon 7b in response to RNA Pol II slowdown, however it fails to do so when the ultra-long-range R2R5 interaction is disrupted. In sum, we demonstrated that mutually exclusive splicing in Ate1 is controlled by two independent, dynamically interacting and functionally distinct RNA structure modules. The molecular mechanism proposed here opens new horizons for the development of therapeutic solutions, including antisense correction of splicing.

scholarly journals Evidence for widespread association of mammalian splicing and conserved long-range RNA structures

RNA ◽  
2011 ◽  
Vol 18 (1) ◽  
pp. 1-15 ◽  
Author(s):  
D. D. Pervouchine ◽  
E. E. Khrameeva ◽  
M. Y. Pichugina ◽  
O. V. Nikolaienko ◽  
M. S. Gelfand ◽  
...  
Keyword(s):  
Long Range ◽  
Rna Structures

Nucleotide composition effects on the long-range correlations in human genes

1998 ◽  
Vol 1 (2) ◽  
pp. 259-263 ◽  
Author(s):  
A. Arnéodo ◽  
Y. d'Aubenton-Carafa ◽  
B. Audit ◽  
E. Bacry ◽  
J.F. Muzy ◽  
...  
Keyword(s):  
Long Range ◽  
Nucleotide Composition ◽  
Long Range Correlations ◽  
Composition Effects ◽  
Human Genes

scholarly journals Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes

2011 ◽  
Vol 108 (27) ◽  
pp. 11093-11098 ◽  
Author(s):  
K. H. Lim ◽  
L. Ferraris ◽  
M. E. Filloux ◽  
B. J. Raphael ◽  
W. G. Fairbrother
Keyword(s):  
Positional Distribution ◽  
Mrna Processing ◽  
Human Genes ◽  
Processing Defects

scholarly journals Multiple competing RNA structures dynamically control alternative splicing in the human ATE1 gene

2020 ◽  
Author(s):  
Marina Kalinina ◽  
Dmitry Skvortsov ◽  
Svetlana Kalmykova ◽  
Timofei Ivanov ◽  
Olga Dontsova ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Long Range ◽  
Rna Structure ◽  
Rna Folding ◽  
Rna Structures ◽  
Tumor Suppressor Function ◽  
Wild Type ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Do So

Abstract The mammalian Ate1 gene encodes an arginyl transferase enzyme with tumor suppressor function that depends on the inclusion of one of the two mutually exclusive exons (MXE), exons 7a and 7b. We report that the molecular mechanism underlying MXE splicing in Ate1 involves five conserved regulatory intronic elements R1–R5, of which R1 and R4 compete for base pairing with R3, while R2 and R5 form an ultra-long-range RNA structure spanning 30 Kb. In minigenes, single and double mutations that disrupt base pairings in R1R3 and R3R4 lead to the loss of MXE splicing, while compensatory triple mutations that restore RNA structure revert splicing to that of the wild type. In the endogenous Ate1 pre-mRNA, blocking the competing base pairings by LNA/DNA mixmers complementary to R3 leads to the loss of MXE splicing, while the disruption of R2R5 interaction changes the ratio of MXE. That is, Ate1 splicing is controlled by two independent, dynamically interacting, and functionally distinct RNA structure modules. Exon 7a becomes more included in response to RNA Pol II slowdown, however it fails to do so when the ultra-long-range R2R5 interaction is disrupted, indicating that exon 7a/7b ratio depends on co-transcriptional RNA folding. In sum, these results demonstrate that splicing is coordinated both in time and in space over very long distances, and that the interaction of these components is mediated by RNA structure.

scholarly journals Conserved long-range RNA structures associated with pre-mRNA processing of human protein-coding genes

2020 ◽  
Author(s):  
Svetlana Kalmykova ◽  
Marina Kalinina ◽  
Stepan Denisov ◽  
Alexey Mironov ◽  
Dmitry Skvortsov ◽  
...  
Keyword(s):  
Long Range ◽  
Rna Folding ◽  
Current Knowledge ◽  
False Positive Rate ◽  
Human Protein ◽  
Circular Rnas ◽  
Splice Sites ◽  
Rna Structures ◽  
Protein Coding ◽  
Protein Coding Genes

AbstractThe 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.

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