Special Issue "Functions and Dynamics of RNA Modifications"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 June 2021).

Special Issue Editors

Dr. Stefanie Kellner
E-Mail Website
Guest Editor
Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 13, DE-81377 Munich, Germany
Interests: RNA; LC-MS; stable isotope labeling; molecular biology; chemical derivatization; electrophoresis; RNA isolation; RNA purification
Dr. Carine Tisne
E-Mail Website1 Website2
Co-Guest Editor
Microbial Gene Expression, Institute of Physico-Chemical Biology, IBPC, 13 rue Pierre et Marie Curie, 75005 Paris, France
Interests: RNA structure; RNA maturation; epitranscriptomics; structural biology; chemistry biology interface; RNA biochemistry
Dr. Pierre Barraud
E-Mail Website
Co-Guest Editor
Microbial Gene Expression, Institute of Physico-Chemical Biology, CNRS, Université de Paris, 13 rue Pierre et Marie Curie, FR-75005 Paris, France
Interests: RNA; protein-RNA complexes; RNA modifications; RNA-binding domains; Nuclear Magnetic Resonance; Molecular Biology; Structural Biology

Special Issue Information

Dear Colleagues,

To fulfil their functions in translation and cell homeostasis, RNA molecules are heavily modified. Chemical variations such as methylations, thiolations or acylations or even rearrangements of the canonical building block form a second layer of information on top of the sequence code. Analogous to the term epigenetics, which describes the modulation of this second layer in DNA, the term epitranscriptomics was established for RNA. In this Special Issue, we will focus on the epitranscriptome and its dynamic character. We welcome submissions of original articles as well as reviews covering all aspects of RNA modification, including the installation of RNA modifications, the active removal of RNA modifications by, e.g., demethylases or RNA degradation, and the impact of these dynamic changes on RNA functions.

Dr. Stefanie Kellner
Dr. Carine Tisne
Dr. Pierre Barraud
Guest Editors

Manuscript Submission Information

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Keywords

  • RNA
  • Epitranscriptome
  • Detection
  • Function
  • Dynamics
  • Biosynthesis
  • RNA degradation
  • Demodification

Published Papers (8 papers)

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Research

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Article
The Stress-Dependent Dynamics of Saccharomyces cerevisiae tRNA and rRNA Modification Profiles
Genes 2021, 12(9), 1344; https://doi.org/10.3390/genes12091344 - 28 Aug 2021
Viewed by 452
Abstract
RNAs are key players in the cell, and to fulfil their functions, they are enzymatically modified. These modifications have been found to be dynamic and dependent on internal and external factors, such as stress. In this study we used nucleic acid isotope labeling [...] Read more.
RNAs are key players in the cell, and to fulfil their functions, they are enzymatically modified. These modifications have been found to be dynamic and dependent on internal and external factors, such as stress. In this study we used nucleic acid isotope labeling coupled mass spectrometry (NAIL-MS) to address the question of which mechanisms allow the dynamic adaptation of RNA modifications during stress in the model organism S. cerevisiae. We found that both tRNA and rRNA transcription is stalled in yeast exposed to stressors such as H2O2, NaAsO2 or methyl methanesulfonate (MMS). From the absence of new transcripts, we concluded that most RNA modification profile changes observed to date are linked to changes happening on the pre-existing RNAs. We confirmed these changes, and we followed the fate of the pre-existing tRNAs and rRNAs during stress recovery. For MMS, we found previously described damage products in tRNA, and in addition, we found evidence for direct base methylation damage of 2′O-ribose methylated nucleosides in rRNA. While we found no evidence for increased RNA degradation after MMS exposure, we observed rapid loss of all methylation damages in all studied RNAs. With NAIL-MS we further established the modification speed in new tRNA and 18S and 25S rRNA from unstressed S. cerevisiae. During stress exposure, the placement of modifications was delayed overall. Only the tRNA modifications 1-methyladenosine and pseudouridine were incorporated as fast in stressed cells as in control cells. Similarly, 2′-O-methyladenosine in both 18S and 25S rRNA was unaffected by the stressor, but all other rRNA modifications were incorporated after a delay. In summary, we present mechanistic insights into stress-dependent RNA modification profiling in S. cerevisiae tRNA and rRNA. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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Article
SMITER—A Python Library for the Simulation of LC-MS/MS Experiments
Genes 2021, 12(3), 396; https://doi.org/10.3390/genes12030396 - 11 Mar 2021
Viewed by 871
Abstract
SMITER (Synthetic mzML writer) is a Python-based command-line tool designed to simulate liquid-chromatography-coupled tandem mass spectrometry LC-MS/MS runs. It enables the simulation of any biomolecule amenable to mass spectrometry (MS) since all calculations are based on chemical formulas. SMITER features a modular design, [...] Read more.
SMITER (Synthetic mzML writer) is a Python-based command-line tool designed to simulate liquid-chromatography-coupled tandem mass spectrometry LC-MS/MS runs. It enables the simulation of any biomolecule amenable to mass spectrometry (MS) since all calculations are based on chemical formulas. SMITER features a modular design, allowing for an easy implementation of different noise and fragmentation models. By default, SMITER uses an established noise model and offers several methods for peptide fragmentation, and two models for nucleoside fragmentation and one for lipid fragmentation. Due to the rich Python ecosystem, other modules, e.g., for retention time (RT) prediction, can easily be implemented for the tailored simulation of any molecule of choice. This facilitates the generation of defined gold-standard LC-MS/MS datasets for any type of experiment. Such gold standards, where the ground truth is known, are required in computational mass spectrometry to test new algorithms and to improve parameters of existing ones. Similarly, gold-standard datasets can be used to evaluate analytical challenges, e.g., by predicting co-elution and co-fragmentation of molecules. As these challenges hinder the detection or quantification of co-eluents, a comprehensive simulation can identify and thus, prevent such difficulties before performing actual MS experiments. SMITER allows the creation of such datasets easily, fast, and efficiently. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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Article
Manganese Ions Individually Alter the Reverse Transcription Signature of Modified Ribonucleosides
Genes 2020, 11(8), 950; https://doi.org/10.3390/genes11080950 - 18 Aug 2020
Cited by 5 | Viewed by 1070
Abstract
Reverse transcription of RNA templates containing modified ribonucleosides transfers modification-related information as misincorporations, arrest or nucleotide skipping events to the newly synthesized cDNA strand. The frequency and proportion of these events, merged from all sequenced cDNAs, yield a so-called RT signature, characteristic for [...] Read more.
Reverse transcription of RNA templates containing modified ribonucleosides transfers modification-related information as misincorporations, arrest or nucleotide skipping events to the newly synthesized cDNA strand. The frequency and proportion of these events, merged from all sequenced cDNAs, yield a so-called RT signature, characteristic for the respective RNA modification and reverse transcriptase (RT). While known for DNA polymerases in so-called error-prone PCR, testing of four different RTs by replacing Mg2+ with Mn2+ in reaction buffer revealed the immense influence of manganese chloride on derived RT signatures, with arrest rates on m1A positions dropping from 82% down to 24%. Additionally, we observed a vast increase in nucleotide skipping events, with single positions rising from 4% to 49%, thus implying an enhanced read-through capability as an effect of Mn2+ on the reverse transcriptase, by promoting nucleotide skipping over synthesis abortion. While modifications such as m1A, m22G, m1G and m3C showed a clear influence of manganese ions on their RT signature, this effect was individual to the polymerase used. In summary, the results imply a supporting effect of Mn2+ on reverse transcription, thus overcoming blockades in the Watson-Crick face of modified ribonucleosides and improving both read-through rate and signal intensity in RT signature analysis. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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Review

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Review
RNA Modifications in Pathogenic Bacteria: Impact on Host Adaptation and Virulence
Genes 2021, 12(8), 1125; https://doi.org/10.3390/genes12081125 - 24 Jul 2021
Viewed by 856
Abstract
RNA modifications are involved in numerous biological processes and are present in all RNA classes. These modifications can be constitutive or modulated in response to adaptive processes. RNA modifications play multiple functions since they can impact RNA base-pairings, recognition by proteins, decoding, as [...] Read more.
RNA modifications are involved in numerous biological processes and are present in all RNA classes. These modifications can be constitutive or modulated in response to adaptive processes. RNA modifications play multiple functions since they can impact RNA base-pairings, recognition by proteins, decoding, as well as RNA structure and stability. However, their roles in stress, environmental adaptation and during infections caused by pathogenic bacteria have just started to be appreciated. With the development of modern technologies in mass spectrometry and deep sequencing, recent examples of modifications regulating host-pathogen interactions have been demonstrated. They show how RNA modifications can regulate immune responses, antibiotic resistance, expression of virulence genes, and bacterial persistence. Here, we illustrate some of these findings, and highlight the strategies used to characterize RNA modifications, and their potential for new therapeutic applications. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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Review
An I for an A: Dynamic Regulation of Adenosine Deamination-Mediated RNA Editing
Genes 2021, 12(7), 1026; https://doi.org/10.3390/genes12071026 - 01 Jul 2021
Cited by 1 | Viewed by 708
Abstract
RNA-editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines in structured RNAs. Inosines are read as guanosines by most cellular machineries. A to I editing has two major functions: first, marking endogenous RNAs as “self”, therefore helping the innate immune [...] Read more.
RNA-editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines in structured RNAs. Inosines are read as guanosines by most cellular machineries. A to I editing has two major functions: first, marking endogenous RNAs as “self”, therefore helping the innate immune system to distinguish repeat- and endogenous retrovirus-derived RNAs from invading pathogenic RNAs; and second, recoding the information of the coding RNAs, leading to the translation of proteins that differ from their genomically encoded versions. It is obvious that these two important biological functions of ADARs will differ during development, in different tissues, upon altered physiological conditions or after exposure to pathogens. Indeed, different levels of ADAR-mediated editing have been observed in different tissues, as a response to altered physiology or upon pathogen exposure. In this review, we describe the dynamics of A to I editing and summarize the known and likely mechanisms that will lead to global but also substrate-specific regulation of A to I editing. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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Review
Analysis of RNA Modifications by Second- and Third-Generation Deep Sequencing: 2020 Update
Genes 2021, 12(2), 278; https://doi.org/10.3390/genes12020278 - 16 Feb 2021
Cited by 8 | Viewed by 1295
Abstract
The precise mapping and quantification of the numerous RNA modifications that are present in tRNAs, rRNAs, ncRNAs/miRNAs, and mRNAs remain a major challenge and a top priority of the epitranscriptomics field. After the keystone discoveries of massive m6A methylation in mRNAs, [...] Read more.
The precise mapping and quantification of the numerous RNA modifications that are present in tRNAs, rRNAs, ncRNAs/miRNAs, and mRNAs remain a major challenge and a top priority of the epitranscriptomics field. After the keystone discoveries of massive m6A methylation in mRNAs, dozens of deep sequencing-based methods and protocols were proposed for the analysis of various RNA modifications, allowing us to considerably extend the list of detectable modified residues. Many of the currently used methods rely on the particular reverse transcription signatures left by RNA modifications in cDNA; these signatures may be naturally present or induced by an appropriate enzymatic or chemical treatment. The newest approaches also include labeling at RNA abasic sites that result from the selective removal of RNA modification or the enhanced cleavage of the RNA ribose-phosphate chain (perhaps also protection from cleavage), followed by specific adapter ligation. Classical affinity/immunoprecipitation-based protocols use either antibodies against modified RNA bases or proteins/enzymes, recognizing RNA modifications. In this survey, we review the most recent achievements in this highly dynamic field, including promising attempts to map RNA modifications by the direct single-molecule sequencing of RNA by nanopores. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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Review
Post-Transcriptional Modifications of Conserved Nucleotides in the T-Loop of tRNA: A Tale of Functional Convergent Evolution
Genes 2021, 12(2), 140; https://doi.org/10.3390/genes12020140 - 22 Jan 2021
Viewed by 587
Abstract
The high conservation of nucleotides of the T-loop, including their chemical identity, are hallmarks of tRNAs from organisms belonging to the three Domains of Life. These structural characteristics allow the T-loop to adopt a peculiar intraloop conformation able to interact specifically with other [...] Read more.
The high conservation of nucleotides of the T-loop, including their chemical identity, are hallmarks of tRNAs from organisms belonging to the three Domains of Life. These structural characteristics allow the T-loop to adopt a peculiar intraloop conformation able to interact specifically with other conserved residues of the D-loop, which ultimately folds the mature tRNA in a unique functional canonical L-shaped architecture. Paradoxically, despite the high conservation of modified nucleotides in the T-loop, enzymes catalyzing their formation depend mostly on the considered organism, attesting for an independent but convergent evolution of the post-transcriptional modification processes. The driving force behind this is the preservation of a native conformation of the tRNA elbow that underlies the various interactions of tRNA molecules with different cellular components. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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Other

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Perspective
The Regulation of RNA Modification Systems: The Next Frontier in Epitranscriptomics?
Genes 2021, 12(3), 345; https://doi.org/10.3390/genes12030345 - 26 Feb 2021
Cited by 2 | Viewed by 929
Abstract
RNA modifications, long considered to be molecular curiosities embellishing just abundant and non-coding RNAs, have now moved into the focus of both academic and applied research. Dedicated research efforts (epitranscriptomics) aim at deciphering the underlying principles by determining RNA modification landscapes and investigating [...] Read more.
RNA modifications, long considered to be molecular curiosities embellishing just abundant and non-coding RNAs, have now moved into the focus of both academic and applied research. Dedicated research efforts (epitranscriptomics) aim at deciphering the underlying principles by determining RNA modification landscapes and investigating the molecular mechanisms that establish, interpret and modulate the information potential of RNA beyond the combination of four canonical nucleotides. This has resulted in mapping various epitranscriptomes at high resolution and in cataloguing the effects caused by aberrant RNA modification circuitry. While the scope of the obtained insights has been complex and exciting, most of current epitranscriptomics appears to be stuck in the process of producing data, with very few efforts to disentangle cause from consequence when studying a specific RNA modification system. This article discusses various knowledge gaps in this field with the aim to raise one specific question: how are the enzymes regulated that dynamically install and modify RNA modifications? Furthermore, various technologies will be highlighted whose development and use might allow identifying specific and context-dependent regulators of epitranscriptomic mechanisms. Given the complexity of individual epitranscriptomes, determining their regulatory principles will become crucially important, especially when aiming at modifying specific aspects of an epitranscriptome both for experimental and, potentially, therapeutic purposes. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
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