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14 pages, 2339 KiB

Open AccessArticle

Insights into Catalytic and tRNA Recognition Mechanism of the Dual-Specific tRNA Methyltransferase from Thermococcus kodakarensis

by Aiswarya Krishnamohan, Samantha Dodbele and Jane E. Jackman

Genes 2019, 10(2), 100; https://doi.org/10.3390/genes10020100 - 30 Jan 2019

Cited by 12 | Viewed by 3570

Abstract

The tRNA methyltransferase Trm10, conserved throughout Eukarya and Archaea, catalyzes N1-methylation of purine residues at position 9 using S-adenosyl methionine as the methyl donor. The Trm10 family exhibits diverse target nucleotide specificity, with some homologs that are obligate m¹G₉ [...] Read more.

The tRNA methyltransferase Trm10, conserved throughout Eukarya and Archaea, catalyzes N1-methylation of purine residues at position 9 using S-adenosyl methionine as the methyl donor. The Trm10 family exhibits diverse target nucleotide specificity, with some homologs that are obligate m¹G₉ or m¹A₉-specific enzymes, while others are bifunctional enzymes catalyzing both m¹G₉ and m¹A₉. This variability is particularly intriguing given different chemical properties of the target N1 atom of guanine and adenine. Here we performed an extensive kinetic and mutational analysis of the m¹G₉ and m¹A₉-catalyzing Trm10 from Thermococcus kodakarensis to gain insight into the active site that facilitates this unique bifunctionality. These results suggest that the rate-determining step for catalysis likely involves a conformational change to correctly position the substrate tRNA in the active site. In this model, kinetic preferences for certain tRNA can be explained by variations in the overall stability of the folded substrate tRNA, consistent with tRNA-specific differences in metal ion dependence. Together, these results provide new insight into the substrate recognition, active site and catalytic mechanism of m¹G/m¹A catalyzing bifunctional enzymes. Full article

(This article belongs to the Special Issue RNA Modifications)

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12 pages, 1334 KiB

Open AccessArticle

Eukaryotic Translation Elongation is Modulated by Single Natural Nucleotide Derivatives in the Coding Sequences of mRNAs

by Thomas Philipp Hoernes, David Heimdörfer, Daniel Köstner, Klaus Faserl, Felix Nußbaumer, Raphael Plangger, Christoph Kreutz, Herbert Lindner and Matthias David Erlacher

Genes 2019, 10(2), 84; https://doi.org/10.3390/genes10020084 - 25 Jan 2019

Cited by 36 | Viewed by 5536

Abstract

RNA modifications are crucial factors for efficient protein synthesis. All classes of RNAs that are involved in translation are modified to different extents. Recently, mRNA modifications and their impact on gene regulation became a focus of interest because they can exert a variety [...] Read more.

RNA modifications are crucial factors for efficient protein synthesis. All classes of RNAs that are involved in translation are modified to different extents. Recently, mRNA modifications and their impact on gene regulation became a focus of interest because they can exert a variety of effects on the fate of mRNAs. mRNA modifications within coding sequences can either directly or indirectly interfere with protein synthesis. In order to investigate the roles of various natural occurring modified nucleotides, we site-specifically introduced them into the coding sequence of reporter mRNAs and subsequently translated them in HEK293T cells. The analysis of the respective protein products revealed a strong position-dependent impact of RNA modifications on translation efficiency and accuracy. Whereas a single 5-methylcytosine (m⁵C) or pseudouridine (Ψ) did not reduce product yields, N¹-methyladenosine (m¹A) generally impeded the translation of the respective modified mRNA. An inhibitory effect of 2′O-methlyated nucleotides (Nm) and N⁶-methyladenosine (m⁶A) was strongly dependent on their position within the codon. Finally, we could not attribute any miscoding potential to the set of mRNA modifications tested in HEK293T cells. Full article

(This article belongs to the Special Issue RNA Modifications)

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9 pages, 1716 KiB

Open AccessArticle

m6A-Dependent RNA Dynamics in T Cell Differentiation

by Mattia Furlan, Eugenia Galeota, Stefano De Pretis, Michele Caselle and Mattia Pelizzola

Genes 2019, 10(1), 28; https://doi.org/10.3390/genes10010028 - 8 Jan 2019

Cited by 31 | Viewed by 5961

Abstract

N6-methyladenosine (m6A) is the most abundant RNA modification. It has been involved in the regulation of RNA metabolism, including degradation and translation, in both physiological and disease conditions. A recent study showed that m6A-mediated degradation of key transcripts also plays a role in [...] Read more.

N6-methyladenosine (m6A) is the most abundant RNA modification. It has been involved in the regulation of RNA metabolism, including degradation and translation, in both physiological and disease conditions. A recent study showed that m6A-mediated degradation of key transcripts also plays a role in the control of T cells homeostasis and IL-7 induced differentiation. We re-analyzed the omics data from that study and, through the integrative analysis of total and nascent RNA-seq data, we were able to comprehensively quantify T cells RNA dynamics and how these are affected by m6A depletion. In addition to the expected impact on RNA degradation, we revealed a broader effect of m6A on RNA dynamics, which included the alteration of RNA synthesis and processing. Altogether, the combined action of m6A on all major steps of the RNA life-cycle closely re-capitulated the observed changes in the abundance of premature and mature RNA species. Ultimately, our re-analysis extended the findings of the initial study, focused on RNA stability, and proposed a yet unappreciated role for m6A in RNA synthesis and processing dynamics. Full article

(This article belongs to the Special Issue RNA Modifications)

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19 pages, 2514 KiB

Open AccessArticle

Production and Application of Stable Isotope-Labeled Internal Standards for RNA Modification Analysis

by Kayla Borland, Jan Diesend, Taku Ito-Kureha, Vigo Heissmeyer, Christian Hammann, Amy H. Buck, Stylianos Michalakis and Stefanie Kellner

Genes 2019, 10(1), 26; https://doi.org/10.3390/genes10010026 - 5 Jan 2019

Cited by 31 | Viewed by 7925

Abstract

Post-transcriptional RNA modifications have been found to be present in a wide variety of organisms and in different types of RNA. Nucleoside modifications are interesting due to their already known roles in translation fidelity, enzyme recognition, disease progression, and RNA stability. In addition, [...] Read more.

Post-transcriptional RNA modifications have been found to be present in a wide variety of organisms and in different types of RNA. Nucleoside modifications are interesting due to their already known roles in translation fidelity, enzyme recognition, disease progression, and RNA stability. In addition, the abundance of modified nucleosides fluctuates based on growth phase, external stress, or possibly other factors not yet explored. With modifications ever changing, a method to determine absolute quantities for multiple nucleoside modifications is required. Here, we report metabolic isotope labeling to produce isotopically labeled internal standards in bacteria and yeast. These can be used for the quantification of 26 different modified nucleosides. We explain in detail how these internal standards are produced and show their mass spectrometric characterization. We apply our internal standards and quantify the modification content of transfer RNA (tRNA) from bacteria and various eukaryotes. We can show that the origin of the internal standard has no impact on the quantification result. Furthermore, we use our internal standard for the quantification of modified nucleosides in mouse tissue messenger RNA (mRNA), where we find different modification profiles in liver and brain tissue. Full article

(This article belongs to the Special Issue RNA Modifications)

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13 pages, 2284 KiB

Open AccessArticle

A-to-I RNA Editing Affects lncRNAs Expression after Heat Shock

by Roni Haas, Nabeel S. Ganem, Ayya Keshet, Angela Orlov, Alla Fishman and Ayelet T. Lamm

Genes 2018, 9(12), 627; https://doi.org/10.3390/genes9120627 - 13 Dec 2018

Cited by 5 | Viewed by 4438

Abstract

Adenosine to inosine (A-to-I) RNA editing is a highly conserved regulatory process carried out by adenosine-deaminases (ADARs) on double-stranded RNA (dsRNAs). Although a considerable fraction of the transcriptome is edited, the function of most editing sites is unknown. Previous studies indicate changes in [...] Read more.

Adenosine to inosine (A-to-I) RNA editing is a highly conserved regulatory process carried out by adenosine-deaminases (ADARs) on double-stranded RNA (dsRNAs). Although a considerable fraction of the transcriptome is edited, the function of most editing sites is unknown. Previous studies indicate changes in A-to-I RNA editing frequencies following exposure to several stress types. However, the overall effect of stress on the expression of ADAR targets is not fully understood. Here, we performed high-throughput RNA sequencing of wild-type and ADAR mutant Caenorhabditis elegans worms after heat-shock to analyze the effect of heat-shock stress on the expression pattern of genes. We found that ADAR regulation following heat-shock does not directly involve heat-shock related genes. Our analysis also revealed that long non-coding RNAs (lncRNAs) and pseudogenes, which have a tendency for secondary RNA structures, are enriched among upregulated genes following heat-shock in ADAR mutant worms. The same group of genes is downregulated in ADAR mutant worms under permissive conditions, which is likely, considering that A-to-I editing protects endogenous dsRNA from RNA-interference (RNAi). Therefore, temperature increases may destabilize dsRNA structures and protect them from RNAi degradation, despite the lack of ADAR function. These findings shed new light on the dynamics of gene expression under heat-shock in relation to ADAR function. Full article

(This article belongs to the Special Issue RNA Modifications)

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8 pages, 2531 KiB

Open AccessArticle

RNA Modification Level Estimation with pulseR

by Etienne Boileau and Christoph Dieterich

Genes 2018, 9(12), 619; https://doi.org/10.3390/genes9120619 - 10 Dec 2018

Cited by 2 | Viewed by 4212

Abstract

RNA modifications regulate the complex life of transcripts. An experimental approach called LAIC-seq was developed to characterize modification levels on a transcriptome-wide scale. In this method, the modified and unmodified molecules are separated using antibodies specific for a given RNA modification (e.g., m [...] Read more.

RNA modifications regulate the complex life of transcripts. An experimental approach called LAIC-seq was developed to characterize modification levels on a transcriptome-wide scale. In this method, the modified and unmodified molecules are separated using antibodies specific for a given RNA modification (e.g., m⁶A). In essence, the procedure of biochemical separation yields three fractions: Input, eluate, and supernatent, which are subjected to RNA-seq. In this work, we present a bioinformatics workflow, which starts from RNA-seq data to infer gene-specific modification levels by a statistical model on a transcriptome-wide scale. Our workflow centers around the pulseR package, which was originally developed for the analysis of metabolic labeling experiments. We demonstrate how to analyze data without external normalization (i.e., in the absence of spike-ins), given high efficiency of separation, and how, alternatively, scaling factors can be derived from unmodified spike-ins. Importantly, our workflow provides an estimate of uncertainty of modification levels in terms of confidence intervals for model parameters, such as gene expression and RNA modification levels. We also compare alternative model parametrizations, log-odds, or the proportion of the modified molecules and discuss the pros and cons of each representation. In summary, our workflow is a versatile approach to RNA modification level estimation, which is open to any read-count-based experimental approach. Full article

(This article belongs to the Special Issue RNA Modifications)

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18 pages, 3673 KiB

Open AccessArticle

Nucleotide Modifications Decrease Innate Immune Response Induced by Synthetic Analogs of snRNAs and snoRNAs

by Grigory Stepanov, Evgenii Zhuravlev, Victoria Shender, Anna Nushtaeva, Evgenia Balakhonova, Elena Mozhaeva, Marat Kasakin, Vladimir Koval, Alexander Lomzov, Marat Pavlyukov, Irina Malyants, Mikhail Zhorov, Tatyana Kabilova, Elena Chernolovskaya, Vadim Govorun, Elena Kuligina, Dmitry Semenov and Vladimir Richter

Genes 2018, 9(11), 531; https://doi.org/10.3390/genes9110531 - 2 Nov 2018

Cited by 32 | Viewed by 4781

Abstract

Short nuclear regulatory RNAs play a key role in the main stages of maturation of the precursors of the major RNA species. Small nuclear RNAs (snRNAs) form the core of the spliceosome and are responsible for the splicing of pre-mRNA molecules. Small nucleolar [...] Read more.

Short nuclear regulatory RNAs play a key role in the main stages of maturation of the precursors of the major RNA species. Small nuclear RNAs (snRNAs) form the core of the spliceosome and are responsible for the splicing of pre-mRNA molecules. Small nucleolar RNAs (snoRNAs) direct post-transcriptional modification of pre-rRNAs. A promising strategy for the development of non-coding RNA (ncRNAs) mimicking molecules is the introduction of modified nucleotides, which are normally present in natural ncRNAs, into the structure of synthetic RNAs. We have created a set of snoRNAs and snRNA analogs and studied the effect of base modifications, specifically, pseudouridine (Ψ) and 5-methylcytidine (m⁵C), on the immune-stimulating and cytotoxic properties of these RNAs. Here, we performed a whole-transcriptome study of the influence of synthetic snoRNA analogs with various modifications on gene expression in human cells. Moreover, we confirmed the role of PKR in the recognition of snoRNA and snRNA analogs using the short hairpin RNA (shRNA) technique. We believe that the data obtained will contribute to the understanding of the role of nucleotide modification in ncRNA functions, and can be useful for creating the agents for gene regulation based on the structure of natural snoRNAs and snRNAs. Full article

(This article belongs to the Special Issue RNA Modifications)

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11 pages, 1396 KiB

Open AccessCommunication

Unfolded Protein Response Suppression in Yeast by Loss of tRNA Modifications

by Alexander Bruch, Roland Klassen and Raffael Schaffrath

Genes 2018, 9(11), 516; https://doi.org/10.3390/genes9110516 - 23 Oct 2018

Cited by 8 | Viewed by 4361

Abstract

Modifications in the anticodon loop of transfer RNAs (tRNAs) have been shown to ensure optimal codon translation rates and prevent protein homeostasis defects that arise in response to translational pausing. Consequently, several yeast mutants lacking important anticodon loop modifications were shown to accumulate [...] Read more.

Modifications in the anticodon loop of transfer RNAs (tRNAs) have been shown to ensure optimal codon translation rates and prevent protein homeostasis defects that arise in response to translational pausing. Consequently, several yeast mutants lacking important anticodon loop modifications were shown to accumulate protein aggregates. Here we analyze whether this includes the activation of the unfolded protein response (UPR), which is commonly triggered by protein aggregation within the endoplasmic reticulum (ER). We demonstrate that two different aggregation prone tRNA modification mutants (elp6 ncs2; elp3 deg1) lacking combinations of 5-methoxycarbonylmethyl-2-thiouridine (mcm⁵s²U: elp3; elp6; ncs2) and pseudouridine (Ψ: deg1) reduce, rather than increase, splicing of HAC1 mRNA, an event normally occurring as a precondition of UPR induction. In addition, tunicamycin (TM) induced HAC1 splicing is strongly impaired in the elp3 deg1 mutant. Strikingly, this mutant displays UPR independent resistance against TM, a phenotype we found to be rescued by overexpression of tRNA^Gln(UUG), the tRNA species usually carrying the mcm⁵s²U34 and Ψ38 modifications. Our data indicate that proper tRNA anticodon loop modifications promote rather than impair UPR activation and reveal that protein synthesis and homeostasis defects in their absence do not routinely result in UPR induction but may relieve endogenous ER stress. Full article

(This article belongs to the Special Issue RNA Modifications)

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Review

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18 pages, 862 KiB

Open AccessReview

RNA Modifications Modulate Activation of Innate Toll-Like Receptors

by Isabel Freund, Tatjana Eigenbrod, Mark Helm and Alexander H. Dalpke

Genes 2019, 10(2), 92; https://doi.org/10.3390/genes10020092 - 29 Jan 2019

Cited by 81 | Viewed by 13366

Abstract

Self/foreign discrimination by the innate immune system depends on receptors that identify molecular patterns as associated to pathogens. Among others, this group includes endosomal Toll-like receptors, among which Toll-like receptors (TLR) 3, 7, 8, and 13 recognize and discriminate mammalian from microbial, potentially [...] Read more.

Self/foreign discrimination by the innate immune system depends on receptors that identify molecular patterns as associated to pathogens. Among others, this group includes endosomal Toll-like receptors, among which Toll-like receptors (TLR) 3, 7, 8, and 13 recognize and discriminate mammalian from microbial, potentially pathogen-associated, RNA. One of the discriminatory principles is the recognition of endogenous RNA modifications. Previous work has identified a couple of RNA modifications that impede activation of TLR signaling when incorporated in synthetic RNA molecules. Of note, work that is more recent has now shown that RNA modifications in their naturally occurring context can have immune-modulatory functions: Gm, a naturally occurring ribose-methylation within tRNA resulted in a lack of TLR7 stimulation and within a defined sequence context acted as antagonist. Additional RNA modifications with immune-modulatory functions have now been identified and recent work also indicates that RNA modifications within the context of whole prokaryotic or eukaryotic cells are indeed used for immune-modulation. This review will discuss new findings and developments in the field of immune-modulatory RNA modifications. Full article

(This article belongs to the Special Issue RNA Modifications)

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15 pages, 2071 KiB

Open AccessReview

m⁶A mRNA Destiny: Chained to the rhYTHm by the YTH-Containing Proteins

by Ditipriya Hazra, Clément Chapat and Marc Graille

Genes 2019, 10(1), 49; https://doi.org/10.3390/genes10010049 - 15 Jan 2019

Cited by 40 | Viewed by 8574

Abstract

The control of gene expression is a multi-layered process occurring at the level of DNA, RNA, and proteins. With the emergence of highly sensitive techniques, new aspects of RNA regulation have been uncovered leading to the emerging field of epitranscriptomics dealing with RNA [...] Read more.

The control of gene expression is a multi-layered process occurring at the level of DNA, RNA, and proteins. With the emergence of highly sensitive techniques, new aspects of RNA regulation have been uncovered leading to the emerging field of epitranscriptomics dealing with RNA modifications. Among those post-transcriptional modifications, N6-methyladenosine (m⁶A) is the most prevalent in messenger RNAs (mRNAs). This mark can either prevent or stimulate the formation of RNA-protein complexes, thereby influencing mRNA-related mechanisms and cellular processes. This review focuses on proteins containing a YTH domain (for YT521-B Homology), a small building block, that selectively detects the m⁶A nucleotide embedded within a consensus motif. Thereby, it contributes to the recruitment of various effectors involved in the control of mRNA fates through adjacent regions present in the different YTH-containing proteins. Full article

(This article belongs to the Special Issue RNA Modifications)

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12 pages, 856 KiB

Open AccessReview

Methods for RNA Modification Mapping Using Deep Sequencing: Established and New Emerging Technologies

by Yuri Motorin and Mark Helm

Genes 2019, 10(1), 35; https://doi.org/10.3390/genes10010035 - 9 Jan 2019

Cited by 86 | Viewed by 10188

Abstract

New analytics of post-transcriptional RNA modifications have paved the way for a tremendous upswing of the biological and biomedical research in this field. This especially applies to methods that included RNA-Seq techniques, and which typically result in what is termed global scale modification [...] Read more.

New analytics of post-transcriptional RNA modifications have paved the way for a tremendous upswing of the biological and biomedical research in this field. This especially applies to methods that included RNA-Seq techniques, and which typically result in what is termed global scale modification mapping. In this process, positions inside a cell’s transcriptome are receiving a status of potential modification sites (so called modification calling), typically based on a score of some kind that issues from the particular method applied. The resulting data are thought to represent information that goes beyond what is contained in typical transcriptome data, and hence the field has taken to use the term “epitranscriptome”. Due to the high rate of newly published mapping techniques, a significant number of chemically distinct RNA modifications have become amenable to mapping, albeit with variegated accuracy and precision, depending on the nature of the technique. This review gives a brief overview of known techniques, and how they were applied to modification calling. Full article

(This article belongs to the Special Issue RNA Modifications)

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16 pages, 1628 KiB

Open AccessReview

Modulation of Bacterial sRNAs Activity by Epigenetic Modifications: Inputs from the Eukaryotic miRNAs

by Brice Felden and David Gilot

Genes 2019, 10(1), 22; https://doi.org/10.3390/genes10010022 - 31 Dec 2018

Cited by 11 | Viewed by 6054

Abstract

Trans-encoded bacterial regulatory RNAs (sRNAs) are functional analogues of eukaryotic microRNAs (miRNAs). These RNA classes act by base-pairing complementarity with their RNA targets to modulate gene expression (transcription, half-life and/or translation). Based on base-pairing, algorithms predict binding and the impact of small RNAs [...] Read more.

Trans-encoded bacterial regulatory RNAs (sRNAs) are functional analogues of eukaryotic microRNAs (miRNAs). These RNA classes act by base-pairing complementarity with their RNA targets to modulate gene expression (transcription, half-life and/or translation). Based on base-pairing, algorithms predict binding and the impact of small RNAs on targeted-RNAs expression and fate. However, other actors are involved such as RNA binding proteins and epigenetic modifications of the targeted and small RNAs. Post-transcriptional base modifications are widespread in all living organisms where they lower undesired RNA folds through conformation adjustments and influence RNA pairing and stability, especially if remodeling their ends. In bacteria, sRNAs possess RNA modifications either internally (methylation, pseudouridinylation) or at their ends. Nicotinamide adenine dinucleotide were detected at 5′-ends, and polyadenylation can occur at 3′-ends. Eukaryotic miRNAs possess N⁶-methyladenosine (m⁶A), A editing into I, and non-templated addition of uridines at their 3′-ends. Biological functions and enzymes involved in those sRNA and micro RNA epigenetic modifications, when known, are presented and challenged. Full article

(This article belongs to the Special Issue RNA Modifications)

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14 pages, 1503 KiB

Open AccessReview

Detection and Analysis of RNA Ribose 2′-O-Methylations: Challenges and Solutions

by Yuri Motorin and Virginie Marchand

Genes 2018, 9(12), 642; https://doi.org/10.3390/genes9120642 - 18 Dec 2018

Cited by 44 | Viewed by 6994

Abstract

Ribose 2′-O-methylation is certainly one of the most common RNA modifications found in almost any type of cellular RNA. It decorates transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs) (and most probably small nucleolar RNAs, snoRNAs), as well as [...] Read more.

Ribose 2′-O-methylation is certainly one of the most common RNA modifications found in almost any type of cellular RNA. It decorates transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs) (and most probably small nucleolar RNAs, snoRNAs), as well as regulatory RNAs like microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), and finally, eukaryotic messenger RNAs (mRNAs). Due to this exceptional widespread of RNA 2′-O-methylation, considerable efforts were made in order to precisely map these numerous modifications. Extensive studies of RNA 2′-O-methylation were also stimulated by the discovery of C/D-box snoRNA-guided machinery, which insures site-specific modification of hundreds 2′-O-methylated residues in archaeal and eukaryotic rRNAs and some other RNAs. In this brief review we discussed both traditional approaches of RNA biochemistry and also modern deep sequencing-based methods, used for detection/mapping and quantification of RNA 2′-O-methylations. Full article

(This article belongs to the Special Issue RNA Modifications)

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11 pages, 1608 KiB

Open AccessReview

N⁶-methyladenosine (m⁶A): Revisiting the Old with Focus on New, an Arabidopsis thaliana Centered Review

by Susheel Sagar Bhat, Dawid Bielewicz, Artur Jarmolowski and Zofia Szweykowska-Kulinska

Genes 2018, 9(12), 596; https://doi.org/10.3390/genes9120596 - 30 Nov 2018

Cited by 29 | Viewed by 6771

Abstract

N⁶-methyladenosine (m⁶A) is known to occur in plant and animal messenger RNAs (mRNAs) since the 1970s. However, the scope and function of this modification remained un-explored till very recently. Since the beginning of this decade, owing to major technological [...] Read more.

N⁶-methyladenosine (m⁶A) is known to occur in plant and animal messenger RNAs (mRNAs) since the 1970s. However, the scope and function of this modification remained un-explored till very recently. Since the beginning of this decade, owing to major technological breakthroughs, the interest in m⁶A has peaked again. Similar to animal mRNAs, plant mRNAs are also m⁶A methylated, within a specific sequence motif which is conserved across these kingdoms. m⁶A has been found to be pivotal for plant development and necessary for processes ranging from seed germination to floral development. A wide range of proteins involved in methylation of adenosine have been identified alongside proteins that remove or identify m⁶A. This review aims to put together the current knowledge regarding m⁶A in Arabidopsis thaliana. Full article

(This article belongs to the Special Issue RNA Modifications)

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28 pages, 1016 KiB

Open AccessReview

Above the Epitranscriptome: RNA Modifications and Stem Cell Identity

by Francesco Morena, Chiara Argentati, Martina Bazzucchi, Carla Emiliani and Sabata Martino

Genes 2018, 9(7), 329; https://doi.org/10.3390/genes9070329 - 28 Jun 2018

Cited by 37 | Viewed by 7716

Abstract

Sequence databases and transcriptome-wide mapping have revealed different reversible and dynamic chemical modifications of the nitrogen bases of RNA molecules. Modifications occur in coding RNAs and noncoding-RNAs post-transcriptionally and they can influence the RNA structure, metabolism, and function. The result is the expansion [...] Read more.

Sequence databases and transcriptome-wide mapping have revealed different reversible and dynamic chemical modifications of the nitrogen bases of RNA molecules. Modifications occur in coding RNAs and noncoding-RNAs post-transcriptionally and they can influence the RNA structure, metabolism, and function. The result is the expansion of the variety of the transcriptome. In fact, depending on the type of modification, RNA molecules enter into a specific program exerting the role of the player or/and the target in biological and pathological processes. Many research groups are exploring the role of RNA modifications (alias epitranscriptome) in cell proliferation, survival, and in more specialized activities. More recently, the role of RNA modifications has been also explored in stem cell biology. Our understanding in this context is still in its infancy. Available evidence addresses the role of RNA modifications in self-renewal, commitment, and differentiation processes of stem cells. In this review, we will focus on five epitranscriptomic marks: N6-methyladenosine, N1-methyladenosine, 5-methylcytosine, Pseudouridine (Ψ) and Adenosine-to-Inosine editing. We will provide insights into the function and the distribution of these chemical modifications in coding RNAs and noncoding-RNAs. Mainly, we will emphasize the role of epitranscriptomic mechanisms in the biology of naïve, primed, embryonic, adult, and cancer stem cells. Full article

(This article belongs to the Special Issue RNA Modifications)

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