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RNA Modifications and Their Role in the Cell Development
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RNA Modifications and Their Role in the Cell Development

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 32619

Special Issue Editor

Dr. Jan Wrzesinski

E-Mail Website
Guest Editor
Institute of Bioorganic Chemistry Polish Academy of Sciences, Poznan, Poland
Interests: RNA; noncoding RNA; DNAzymes and ribozymes; modified nucleotides; metal ions

Special Issue Information

Dear Colleagues

It is well documented that RNA molecules perform various functions in the gene expression processes in the cell. So far, over 100 modified nucleotides found in many types of RNA, i.e., rRNA, tRNA, mRNA, lncRNA, have been identified, including those resulting from the simple methylation of the 2'OH ribose group as well as hypermodified pyrimidine and purine bases of such as mnm5s2U, sc4C, i6A, and Y.

The biosynthesis of some modified nucleotides in RNA (epitranscriptome) has only partly been explored. In addition to nucleotide-modifying enzymes (writers), there are also enzymes that remove modifications (erasers) and proteins that recognize RNA modifications (readers). Understanding these processes and their dependence on the stages of cell development and carcinogenesis is a major challenge of molecular genomics.

Moreover, the function of RNA modifications in the cell has not been fully elucidated. Current research shows their important role in cellular processes such as translation, interaction with proteins, ensuring RNA stability, etc.

For this Special Issue, we ask for comprehensive reviews, original research manuscripts, and methodological articles.

Dr. Jan Wrzesinski
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • RNA
  • Epitranscriptome
  • Modified nucleotides detection and characterization
  • Writer, reader, and eraser enzymes and proteins
  • Modified nucleotide–protein interaction
  • Gene expression

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Published Papers (7 papers)

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Research

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17 pages, 7085 KiB  
Article
Loss of Cnot6l Impairs Inosine RNA Modifications in Mouse Oocytes
by Pavla Brachova, Nehemiah S. Alvarez and Lane K. Christenson
Int. J. Mol. Sci. 2021, 22(3), 1191; https://doi.org/10.3390/ijms22031191 - 26 Jan 2021
Cited by 8 | Viewed by 2782
Abstract
Mammalian oocytes must degrade maternal transcripts through a process called translational mRNA decay, in which maternal mRNA undergoes translational activation, followed by deadenylation and mRNA decay. Once a transcript is translationally activated, it becomes deadenylated by the CCR4-NOT complex. Knockout of CCR4-NOT Transcription [...] Read more.
Mammalian oocytes must degrade maternal transcripts through a process called translational mRNA decay, in which maternal mRNA undergoes translational activation, followed by deadenylation and mRNA decay. Once a transcript is translationally activated, it becomes deadenylated by the CCR4-NOT complex. Knockout of CCR4-NOT Transcription Complex Subunit 6 Like (Cnot6l), a deadenylase within the CCR4-NOT complex, results in mRNA decay defects during metaphase I (MI) entry. Knockout of B-cell translocation gene-4 (Btg4), an adaptor protein of the CCR4-NOT complex, results in mRNA decay defects following fertilization. Therefore, mechanisms controlling mRNA turnover have significant impacts on oocyte competence and early embryonic development. Post-transcriptional inosine RNA modifications can impact mRNA stability, possibly through a translation mechanism. Here, we assessed inosine RNA modifications in oocytes, eggs, and embryos from Cnot6l-/- and Btg4-/- mice, which display stabilization of mRNA and over-translation of the stabilized transcripts. If inosine modifications have a role in modulating RNA stability, we hypothesize that in these mutant backgrounds, we would observe changes or a disruption in inosine mRNA modifications. To test this, we used a computational approach to identify inosine RNA modifications in total and polysomal RNA-seq data during meiotic maturation (GV, MI, and MII stages). We observed pronounced depletion of inosine mRNA modifications in samples from Cnot6l-/-, but not in Btg4-/- mice. Additionally, analysis of ribosome-associated RNA revealed clearance of inosine modified mRNA. These observations suggest a novel mechanism of mRNA clearance during oocyte maturation, in which inosine-containing transcripts decay in an independent, but parallel mechanism to CCR4-NOT deadenylation. Full article
(This article belongs to the Special Issue RNA Modifications and Their Role in the Cell Development)
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Review

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43 pages, 4831 KiB  
Review
Advances in Computational Methodologies for Classification and Sub-Cellular Locality Prediction of Non-Coding RNAs
by Muhammad Nabeel Asim, Muhammad Ali Ibrahim, Muhammad Imran Malik, Andreas Dengel and Sheraz Ahmed
Int. J. Mol. Sci. 2021, 22(16), 8719; https://doi.org/10.3390/ijms22168719 - 13 Aug 2021
Cited by 17 | Viewed by 4540
Abstract
Apart from protein-coding Ribonucleic acids (RNAs), there exists a variety of non-coding RNAs (ncRNAs) which regulate complex cellular and molecular processes. High-throughput sequencing technologies and bioinformatics approaches have largely promoted the exploration of ncRNAs which revealed their crucial roles in gene regulation, miRNA [...] Read more.
Apart from protein-coding Ribonucleic acids (RNAs), there exists a variety of non-coding RNAs (ncRNAs) which regulate complex cellular and molecular processes. High-throughput sequencing technologies and bioinformatics approaches have largely promoted the exploration of ncRNAs which revealed their crucial roles in gene regulation, miRNA binding, protein interactions, and splicing. Furthermore, ncRNAs are involved in the development of complicated diseases like cancer. Categorization of ncRNAs is essential to understand the mechanisms of diseases and to develop effective treatments. Sub-cellular localization information of ncRNAs demystifies diverse functionalities of ncRNAs. To date, several computational methodologies have been proposed to precisely identify the class as well as sub-cellular localization patterns of RNAs). This paper discusses different types of ncRNAs, reviews computational approaches proposed in the last 10 years to distinguish coding-RNA from ncRNA, to identify sub-types of ncRNAs such as piwi-associated RNA, micro RNA, long ncRNA, and circular RNA, and to determine sub-cellular localization of distinct ncRNAs and RNAs. Furthermore, it summarizes diverse ncRNA classification and sub-cellular localization determination datasets along with benchmark performance to aid the development and evaluation of novel computational methodologies. It identifies research gaps, heterogeneity, and challenges in the development of computational approaches for RNA sequence analysis. We consider that our expert analysis will assist Artificial Intelligence researchers with knowing state-of-the-art performance, model selection for various tasks on one platform, dominantly used sequence descriptors, neural architectures, and interpreting inter-species and intra-species performance deviation. Full article
(This article belongs to the Special Issue RNA Modifications and Their Role in the Cell Development)
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14 pages, 515 KiB  
Review
Adaptor Molecules Epitranscriptome Reprograms Bacterial Pathogenicity
by Adamantia Kouvela, Apostolos Zaravinos and Vassiliki Stamatopoulou
Int. J. Mol. Sci. 2021, 22(16), 8409; https://doi.org/10.3390/ijms22168409 - 5 Aug 2021
Cited by 2 | Viewed by 2658
Abstract
The strong decoration of tRNAs with post-transcriptional modifications provides an unprecedented adaptability of this class of non-coding RNAs leading to the regulation of bacterial growth and pathogenicity. Accumulating data indicate that tRNA post-transcriptional modifications possess a central role in both the formation of [...] Read more.
The strong decoration of tRNAs with post-transcriptional modifications provides an unprecedented adaptability of this class of non-coding RNAs leading to the regulation of bacterial growth and pathogenicity. Accumulating data indicate that tRNA post-transcriptional modifications possess a central role in both the formation of bacterial cell wall and the modulation of transcription and translation fidelity, but also in the expression of virulence factors. Evolutionary conserved modifications in tRNA nucleosides ensure the proper folding and stability redounding to a totally functional molecule. However, environmental factors including stress conditions can cause various alterations in tRNA modifications, disturbing the pathogen homeostasis. Post-transcriptional modifications adjacent to the anticodon stem-loop, for instance, have been tightly linked to bacterial infectivity. Currently, advances in high throughput methodologies have facilitated the identification and functional investigation of such tRNA modifications offering a broader pool of putative alternative molecular targets and therapeutic avenues against bacterial infections. Herein, we focus on tRNA epitranscriptome shaping regarding modifications with a key role in bacterial infectivity including opportunistic pathogens of the human microbiome. Full article
(This article belongs to the Special Issue RNA Modifications and Their Role in the Cell Development)
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20 pages, 1232 KiB  
Review
Application of Modified mRNA in Somatic Reprogramming to Pluripotency and Directed Conversion of Cell Fate
by Aline Yen Ling Wang
Int. J. Mol. Sci. 2021, 22(15), 8148; https://doi.org/10.3390/ijms22158148 - 29 Jul 2021
Cited by 19 | Viewed by 4968
Abstract
Modified mRNA (modRNA)-based somatic reprogramming is an effective and safe approach that overcomes the genomic mutation risk caused by viral integrative methods. It has improved the disadvantages of conventional mRNA and has better stability and immunogenicity. The modRNA molecules encoding multiple pluripotent factors [...] Read more.
Modified mRNA (modRNA)-based somatic reprogramming is an effective and safe approach that overcomes the genomic mutation risk caused by viral integrative methods. It has improved the disadvantages of conventional mRNA and has better stability and immunogenicity. The modRNA molecules encoding multiple pluripotent factors have been applied successfully in reprogramming somatic cells such as fibroblasts, mesenchymal stem cells, and amniotic fluid stem cells to generate pluripotent stem cells (iPSCs). Moreover, it also can be directly used in the terminal differentiation of stem cells and fibroblasts into functional therapeutic cells, which exhibit great promise in disease modeling, drug screening, cell transplantation therapy, and regenerative medicine. In this review, we summarized the reprogramming applications of modified mRNA in iPSC generation and therapeutic applications of functionally differentiated cells. Full article
(This article belongs to the Special Issue RNA Modifications and Their Role in the Cell Development)
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19 pages, 1223 KiB  
Review
Long Non-Coding RNA Epigenetics
by Marek Kazimierczyk and Jan Wrzesinski
Int. J. Mol. Sci. 2021, 22(11), 6166; https://doi.org/10.3390/ijms22116166 - 7 Jun 2021
Cited by 31 | Viewed by 5951
Abstract
Long noncoding RNAs exceeding a length of 200 nucleotides play an important role in ensuring cell functions and proper organism development by interacting with cellular compounds such as miRNA, mRNA, DNA and proteins. However, there is an additional level of lncRNA regulation, called [...] Read more.
Long noncoding RNAs exceeding a length of 200 nucleotides play an important role in ensuring cell functions and proper organism development by interacting with cellular compounds such as miRNA, mRNA, DNA and proteins. However, there is an additional level of lncRNA regulation, called lncRNA epigenetics, in gene expression control. In this review, we describe the most common modified nucleosides found in lncRNA, 6-methyladenosine, 5-methylcytidine, pseudouridine and inosine. The biosynthetic pathways of these nucleosides modified by the writer, eraser and reader enzymes are important to understanding these processes. The characteristics of the individual methylases, pseudouridine synthases and adenine–inosine editing enzymes and the methods of lncRNA epigenetics for the detection of modified nucleosides, as well as the advantages and disadvantages of these methods, are discussed in detail. The final sections are devoted to the role of modifications in the most abundant lncRNAs and their functions in pathogenic processes. Full article
(This article belongs to the Special Issue RNA Modifications and Their Role in the Cell Development)
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12 pages, 1135 KiB  
Review
Regulation of Ribosome Function by RNA Modifications in Hematopoietic Development and Leukemia: It Is Not Only a Matter of m6A
by Francesco Fazi and Alessandro Fatica
Int. J. Mol. Sci. 2021, 22(9), 4755; https://doi.org/10.3390/ijms22094755 - 30 Apr 2021
Cited by 5 | Viewed by 3247
Abstract
Growth and maturation of hematopoietic stem cells (HSCs) are largely controlled at both transcriptional and post-transcriptional levels. In particular, hematopoietic development requires a tight control of protein synthesis. Furthermore, translational deregulation strongly contributes to hematopoietic malignancies. Researchers have recently identified a new layer [...] Read more.
Growth and maturation of hematopoietic stem cells (HSCs) are largely controlled at both transcriptional and post-transcriptional levels. In particular, hematopoietic development requires a tight control of protein synthesis. Furthermore, translational deregulation strongly contributes to hematopoietic malignancies. Researchers have recently identified a new layer of gene expression regulation that consists of chemical modification of RNA species, which led to the birth of the epitranscriptomics field. RNA modifications provide an additional level of control in hematopoietic development by acting as post-transcriptional regulators of lineage-specific genetic programs. Other reviews have already described the important role of the N6-methylation of adenosine (m6A) within mRNA species in regulating hematopoietic differentiation and diseases. The aim of this review is to summarize the current status of the role of RNA modifications in the regulation of ribosome function, beyond m6A. In particular, we discuss the importance of RNA modifications in tRNA and rRNA molecules. By balancing translational rate and fidelity, they play an important role in regulating normal and malignant hematopoietic development. Full article
(This article belongs to the Special Issue RNA Modifications and Their Role in the Cell Development)
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21 pages, 4814 KiB  
Review
METTL16, Methyltransferase-Like Protein 16: Current Insights into Structure and Function
by Agnieszka Ruszkowska
Int. J. Mol. Sci. 2021, 22(4), 2176; https://doi.org/10.3390/ijms22042176 - 22 Feb 2021
Cited by 64 | Viewed by 7071
Abstract
Methyltransferase-like protein 16 (METTL16) is a human RNA methyltransferase that installs m6A marks on U6 small nuclear RNA (U6 snRNA) and S-adenosylmethionine (SAM) synthetase pre-mRNA. METTL16 also controls a significant portion of m6A epitranscriptome by regulating SAM homeostasis. [...] Read more.
Methyltransferase-like protein 16 (METTL16) is a human RNA methyltransferase that installs m6A marks on U6 small nuclear RNA (U6 snRNA) and S-adenosylmethionine (SAM) synthetase pre-mRNA. METTL16 also controls a significant portion of m6A epitranscriptome by regulating SAM homeostasis. Multiple molecular structures of the N-terminal methyltransferase domain of METTL16, including apo forms and complexes with S-adenosylhomocysteine (SAH) or RNA, provided the structural basis of METTL16 interaction with the coenzyme and substrates, as well as indicated autoinhibitory mechanism of the enzyme activity regulation. Very recent structural and functional studies of vertebrate-conserved regions (VCRs) indicated their crucial role in the interaction with U6 snRNA. METTL16 remains an object of intense studies, as it has been associated with numerous RNA classes, including mRNA, non-coding RNA, long non-coding RNA (lncRNA), and rRNA. Moreover, the interaction between METTL16 and oncogenic lncRNA MALAT1 indicates the existence of METTL16 features specifically recognizing RNA triple helices. Overall, the number of known human m6A methyltransferases has grown from one to five during the last five years. METTL16, CAPAM, and two rRNA methyltransferases, METTL5/TRMT112 and ZCCHC4, have joined the well-known METTL3/METTL14. This work summarizes current knowledge about METTL16 in the landscape of human m6A RNA methyltransferases. Full article
(This article belongs to the Special Issue RNA Modifications and Their Role in the Cell Development)
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