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RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases

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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 31269

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Special Issue Editor

Prof. Dr. Shih-Hwa Chiou

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Guest Editor

Genomics Research Ceter, Academia Sinica, National Yang-Ming University, Taipei, Taiwan
Interests: epigenetics; stem cell biology; genetic engineering in translational medicine

Special Issue Information

Dear Colleagues,

Looking back on the developing trends in the field of epigenetics, modification on histones, DNA and RNA one after another demonstrates their role in orchestrating cell fates. RNA modification is of note, the recent hot topic that has been linked toward regulation of ontogeny, hematopoiesis, inflammation and immunity commitment. Strikingly, the decoration of RNA was found not merely a simple chemical additive to nucleotide, but a powerful switch that harness spatiotemporal conformation of the gene transcriptome. In this Special Issue, we will include original articles and comprehensive reviews to elucidate how RNA modifications such as m6A, m1A, and m7G could link RNA dynamics toward cellular dysregulation and diseases. To date, more than 160 chemical modifications on ribonucleosides have been identified. They exist on ribosomal RNA, transfer RNA, messenger RNA and various noncoding RNAs. Similarly to epigenetic modifications on histones and DNA, modifications on RNA could regulate gene expression and phenotypes without affecting the DNA sequence. Hence, RNA modifications have been considered as a new defined fine-tuning layer as to the gene regulation. Thus, many dysregulation of RNA modifications have been linked toward disturbed cellular homeostasis. In order to provide readers with a holistic view of the influence of RNA modifications in cellular dysfunction, authors from this Special Issue will address their research experience in terms of bio-chemical techniques, phenotypic characterization and strategies in the molecular biology approach.

Prof. Dr. Shih-Hwa Chiou
Guest Editor

Manuscript Submission Information

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Keywords

RNA modification
Cellular stress response
Epi-transcriptomes in disease models

Published Papers (7 papers)

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Research

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15 pages, 1324 KiB

Open AccessArticle

Integrative Analyses of Circulating Small RNAs and Kidney Graft Transcriptome in Transplant Glomerulopathy

by Canan Kuscu, Manjari Kiran, Akram Mohammed, Cem Kuscu, Sarthak Satpathy, Aaron Wolen, Elissa Bardhi, Amandeep Bajwa, James D. Eason, Daniel Maluf, Valeria Mas and Enver Akalin

Int. J. Mol. Sci. 2021, 22(12), 6218; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126218 - 09 Jun 2021

Cited by 8 | Viewed by 2865

Abstract

Transplant glomerulopathy develops through multiple mechanisms, including donor-specific antibodies, T cells and innate immunity. This study investigates circulating small RNA profiles in serum samples of kidney transplant recipients with biopsy-proven transplant glomerulopathy. Among total small RNA population, miRNAs were the most abundant species in the serum of kidney transplant patients. In addition, fragments arising from mature tRNA and rRNA were detected. Most of the tRNA fragments were generated from 5′ ends of mature tRNA and mainly from two parental tRNAs: tRNA-Gly and tRNA-Glu. Moreover, transplant patients with transplant glomerulopathy displayed a novel tRNA fragments signature. Gene expression analysis from allograft tissues demonstrated changes in canonical pathways related to immune activation such as iCos-iCosL signaling pathway in T helper cells, Th1 and Th2 activation pathway, and dendritic cell maturation. mRNA targets of down-regulated miRNAs such as miR-1224-5p, miR-4508, miR-320, miR-378a from serum were globally upregulated in tissue. Integration of serum miRNA profiles with tissue gene expression showed that changes in serum miRNAs support the role of T-cell mediated mechanisms in ongoing allograft injury. Full article

(This article belongs to the Special Issue RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases)

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15 pages, 9671 KiB

Open AccessArticle

An Integrated Transcriptomic Approach to Identify Molecular Markers of Calcineurin Inhibitor Nephrotoxicity in Pediatric Kidney Transplant Recipients

by Erika T. Rhone, Elissa Bardhi, Sai Vineela Bontha, Patrick D. Walker, Jorge A. Almenara, Catherine I. Dumur, Helen Cathro, Daniel Maluf and Valeria Mas

Int. J. Mol. Sci. 2021, 22(11), 5414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115414 - 21 May 2021

Cited by 1 | Viewed by 2408

Abstract

Calcineurin inhibitors are highly efficacious immunosuppressive agents used in pediatric kidney transplantation. However, calcineurin inhibitor nephrotoxicity (CNIT) has been associated with the development of chronic renal allograft dysfunction and decreased graft survival. This study evaluated 37 formalin-fixed paraffin-embedded biopsies from pediatric kidney transplant recipients using gene expression profiling. Normal allograft samples (n = 12) served as negative controls and were compared to biopsies exhibiting CNIT (n = 11). The remaining samples served as positive controls to validate CNIT marker specificity and were characterized by other common causes of graft failure such as acute rejection (n = 7) and interstitial fibrosis/tubular atrophy (n = 7). MiRNA profiles served as the platform for data integration. Oxidative phosphorylation and mitochondrial dysfunction were the top molecular pathways associated with overexpressed genes in CNIT samples. Decreased ATP synthesis was identified as a significant biological function in CNIT, while key toxicology pathways included NRF2-mediated oxidative stress response and increased permeability transition of mitochondria. An integrative analysis demonstrated a panel of 13 significant miRNAs and their 33 CNIT-specific gene targets involved with mitochondrial activity and function. We also identified a candidate panel of miRNAs/genes, which may serve as future molecular markers for CNIT diagnosis as well as potential therapeutic targets. Full article

(This article belongs to the Special Issue RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases)

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Review

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23 pages, 2503 KiB

Open AccessReview

FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms

by Sarah Kassem Azzam, Habiba Alsafar and Abdulrahim A. Sajini

Int. J. Mol. Sci. 2022, 23(7), 3800; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073800 - 30 Mar 2022

Cited by 55 | Viewed by 7977

Abstract

Fat mass and obesity-associated protein (FTO) is the first reported RNA N6-methyladenosine (m6A) demethylase in eukaryotic cells. m6A is considered as the most abundant mRNA internal modification, which modulates several cellular processes including alternative splicing, stability, and expression. Genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) within FTO to be associated with obesity, as well as cancer including endometrial cancer, breast cancer, pancreatic cancer, and melanoma. Since the initial classification of FTO as an m6A demethylase, various studies started to unravel a connection between FTO’s demethylase activity and the susceptibility to obesity on the molecular level. FTO was found to facilitate adipogenesis, by regulating adipogenic pathways and inducing pre-adipocyte differentiation. FTO has also been investigated in tumorigenesis, where emerging studies suggest m6A and FTO levels are dysregulated in various cancers, including acute myeloid leukemia (AML), glioblastoma, cervical squamous cell carcinoma (CSCC), breast cancer, and melanoma. Here we review the molecular bases of m6A in tumorigenesis and adipogenesis while highlighting the controversial role of FTO in obesity. We provide recent findings confirming FTO’s causative link to obesity and discuss novel approaches using RNA demethylase inhibitors as targeted oncotherapies. Our review aims to confirm m6A demethylation as a risk factor in obesity and provoke new research in FTO and human disorders. Full article

(This article belongs to the Special Issue RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases)

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16 pages, 1674 KiB

Open AccessReview

Biosynthesis and Degradation of Sulfur Modifications in tRNAs

by Naoki Shigi

Int. J. Mol. Sci. 2021, 22(21), 11937; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111937 - 03 Nov 2021

Cited by 11 | Viewed by 3174

Abstract

Various sulfur-containing biomolecules include iron–sulfur clusters that act as cofactors for enzymes, sulfur-containing vitamins such as thiamin, and sulfur-modified nucleosides in RNA, in addition to methionine and cysteine in proteins. Sulfur-containing nucleosides are post-transcriptionally introduced into tRNA molecules, where they ensure precise codon recognition or stabilization of tRNA structure, thereby maintaining cellular proteome integrity. Modulating sulfur modification controls the translation efficiency of specific groups of genes, allowing organisms to adapt to specific environments. The biosynthesis of tRNA sulfur nucleosides involves elaborate ‘sulfur trafficking systems’ within cellular sulfur metabolism and ‘modification enzymes’ that incorporate sulfur atoms into tRNA. This review provides an up-to-date overview of advances in our knowledge of the mechanisms involved. It covers the functions, biosynthesis, and biodegradation of sulfur-containing nucleosides as well as the reaction mechanisms of biosynthetic enzymes catalyzed by the iron–sulfur clusters, and identification of enzymes involved in the de-modification of sulfur atoms of RNA. The mechanistic similarity of these opposite reactions is discussed. Mutations in genes related to these pathways can cause human diseases (e.g., cancer, diabetes, and mitochondrial diseases), emphasizing the importance of these pathways. Full article

(This article belongs to the Special Issue RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases)

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25 pages, 1004 KiB

Open AccessReview

RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

by Biswanath Chatterjee, Che-Kun James Shen and Pritha Majumder

Int. J. Mol. Sci. 2021, 22(21), 11870; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111870 - 01 Nov 2021

Cited by 24 | Viewed by 3820

Abstract

The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on the dynamic nature and spatiotemporal patterning of gene expression. These features of gene expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, and non-coding RNA activity, amongst others. In concert, another regulatory layer by which RNA bases and sugar residues are chemically modified enhances neuronal transcriptome complexity. Similar RNA modifications in other systems collectively constitute the cellular epitranscriptome that integrates and impacts various physiological processes. The epitranscriptome is dynamic and is reshaped constantly to regulate vital processes such as development, differentiation and stress responses. Perturbations of the epitranscriptome can lead to various pathogenic conditions, including cancer, cardiovascular abnormalities and neurological diseases. Recent advances in next-generation sequencing technologies have enabled us to identify and locate modified bases/sugars on different RNA species. These RNA modifications modulate the stability, transport and, most importantly, translation of RNA. In this review, we discuss the formation and functions of some frequently observed RNA modifications—including methylations of adenine and cytosine bases, and isomerization of uridine to pseudouridine—at various layers of RNA metabolism, together with their contributions to abnormal physiological conditions that can lead to various neurodevelopmental and neurological disorders. Full article

(This article belongs to the Special Issue RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases)

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17 pages, 1460 KiB

Open AccessReview

RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases

by Takashi Hosaka, Hiroshi Tsuji and Shin Kwak

Int. J. Mol. Sci. 2021, 22(20), 10958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010958 - 11 Oct 2021

Cited by 12 | Viewed by 3575

Abstract

The conversion of adenosine to inosine in RNA editing (A-to-I RNA editing) is recognized as a critical post-transcriptional modification of RNA by adenosine deaminases acting on RNAs (ADARs). A-to-I RNA editing occurs predominantly in mammalian and human central nervous systems and can alter the function of translated proteins, including neurotransmitter receptors and ion channels; therefore, the role of dysregulated RNA editing in the pathogenesis of neurological diseases has been speculated. Specifically, the failure of A-to-I RNA editing at the glutamine/arginine (Q/R) site of the GluA2 subunit causes excessive permeability of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to Ca²⁺, inducing fatal status epilepticus and the neurodegeneration of motor neurons in mice. Therefore, an RNA editing deficiency at the Q/R site in GluA2 due to the downregulation of ADAR2 in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients suggests that Ca²⁺-permeable AMPA receptors and the dysregulation of RNA editing are suitable therapeutic targets for ALS. Gene therapy has recently emerged as a new therapeutic opportunity for many heretofore incurable diseases, and RNA editing dysregulation can be a target for gene therapy; therefore, we reviewed neurological diseases associated with dysregulated RNA editing and a new therapeutic approach targeting dysregulated RNA editing, especially one that is effective in ALS. Full article

(This article belongs to the Special Issue RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases)

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20 pages, 4277 KiB

Open AccessReview

RNA Modifications and Epigenetics in Modulation of Lung Cancer and Pulmonary Diseases

by Pai-Chi Teng, Yanwen Liang, Aliaksandr A. Yarmishyn, Yu-Jer Hsiao, Ting-Yi Lin, Tzu-Wei Lin, Yuan-Chi Teng, Yi-Ping Yang, Mong-Lien Wang, Chian-Shiu Chien, Yung-Hung Luo, Yuh-Min Chen, Po-Kuei Hsu, Shih-Hwa Chiou and Yueh Chien

Int. J. Mol. Sci. 2021, 22(19), 10592; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910592 - 30 Sep 2021

Cited by 59 | Viewed by 6496

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves the accumulation of genetic and epigenetic events in the respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, and histone modifications, have been widely reported to play an important role in lung cancer development and in other pulmonary diseases. Whereas the functionality of DNA and chromatin modifications referred to as epigenetics is widely characterized, various modifications of RNA nucleotides have recently come into prominence as functionally important. N6-methyladosine (m6A) is the most prevalent internal modification in mRNAs, and its machinery of writers, erasers, and readers is well-characterized. However, several other nucleotide modifications of mRNAs and various noncoding RNAs have also been shown to play an important role in the regulation of biological processes and pathology. Such epitranscriptomic modifications play an important role in regulating various aspects of RNA metabolism, including transcription, translation, splicing, and stability. The dysregulation of epitranscriptomic machinery has been implicated in the pathological processes associated with carcinogenesis including uncontrolled cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, with the advancement of RNA sequencing technology, high-resolution maps of different modifications in various tissues, organs, or disease models are being constantly reported at a dramatic speed. This facilitates further understanding of the relationship between disease development and epitranscriptomics, shedding light on new therapeutic possibilities. In this review, we summarize the basic information on RNA modifications, including m6A, m1A, m5C, m7G, pseudouridine, and A-to-I editing. We then demonstrate their relation to different kinds of lung diseases, especially lung cancer. By comparing the different roles RNA modifications play in the development processes of different diseases, this review may provide some new insights and offer a better understanding of RNA epigenetics and its involvement in pulmonary diseases. Full article

(This article belongs to the Special Issue RNA Modification Dynamics in Cellular Dysregulation and Clinical Diseases)

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