Non-coding RNAs in Cellular Differentiation, Development, and Diseases

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Biochemistry, Biophysics and Computational Biology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 24018

Special Issue Editors


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Guest Editor
Department of Biological Sciences, University at Albany, State University of New York (SUNY), Albany, NY 12222, USA
Interests: non-coding RNAs; muscle degenerative diseases
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Co-Guest Editor
School of Medicine, National University of Ireland Galway, University Road, Galway H91 TK33, Ireland
Interests: endoplasmic reticulum stress; unfolded protein response; tumour microenvironment; XBP1; endocrine resistance; microRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the discovery of the genetic code, the primary paradigm has been that a DNA blueprint encodes RNA messengers, which are then translated into functional proteins. The proteins were considered as the ultimate workhorses in this hierarchy. In the last three decades, however, the paradigm that proteins are the sole players of the genetic code has changed. With the release of the human genome sequence and transcriptome analyses, it has become clear that only a small fraction of the genome encodes proteins. The large proportion of the non-protein-coding genome gives rise to various regulatory RNA molecules, collectively known as non-coding RNAs (ncRNAs). Although the ncRNAs were considered as evolutionary junk in the past, cumulative evidence suggests the significant impact of these molecules in numerous biological functions, including cellular differentiation, development, and disease.

Diverse classes of non-coding RNAs have been identified in the mammalian genome, broadly classified based on their length as small and long ncRNAs. Small ncRNAs are again classified as micro and non-micro small RNAs. MicroRNAs regulate post-transcriptional gene expression and are implicated in almost all aspects of biological processes. The non-micro small RNAs are relatively new but seem to have critical biological functions. On the other hand, long ncRNAs play a biological role through diverse mechanisms. Long ncRNAs are versatile molecules that can interact physically with DNA, protein, and RNA either through nucleotide base pairing or via the formation of a secondary structure and regulation of gene expression. Growing evidence suggests that non-coding RNAs regulate almost every necessary cellular process, and the expression of these molecules is strictly regulated in normal physiological conditions. Since the expression of ncRNAs is dysregulated in numerous human diseases, these molecules have a great potential to be used as a new generation of therapeutic and diagnostic molecules.

This Special Issue aims to publish research and review articles covering the verities of these ncRNA molecules in differentiation, development, and disease.

Dr. Bijan K. Dey
Dr. Sanjeev Gupta
Guest Editors

Manuscript Submission Information

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Keywords

  • non-coding RNAs
  • microRNAs
  • small RNAs
  • differentiation
  • development
  • regeneration
  • disease
  • therapeutics
  • diagnostics

Published Papers (10 papers)

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Research

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16 pages, 1431 KiB  
Article
NSD1 Mutations in Sotos Syndrome Induce Differential Expression of Long Noncoding RNAs, miR646 and Genes Controlling the G2/M Checkpoint
by Giuseppina Conteduca, Davide Cangelosi, Simona Coco, Michela Malacarne, Chiara Baldo, Alessia Arado, Rute Pinto, Barbara Testa and Domenico A. Coviello
Life 2022, 12(7), 988; https://doi.org/10.3390/life12070988 - 02 Jul 2022
Cited by 4 | Viewed by 2402
Abstract
An increasing amount of evidence indicates the critical role of the NSD1 gene in Sotos syndrome (SoS), a rare genetic disease, and in tumors. Molecular mechanisms affected by NSD1 mutations are largely uncharacterized. In order to assess the impact of NSD1 haploinsufficiency in [...] Read more.
An increasing amount of evidence indicates the critical role of the NSD1 gene in Sotos syndrome (SoS), a rare genetic disease, and in tumors. Molecular mechanisms affected by NSD1 mutations are largely uncharacterized. In order to assess the impact of NSD1 haploinsufficiency in the pathogenesis of SoS, we analyzed the gene expression profile of fibroblasts isolated from the skin samples of 15 SoS patients and of 5 healthy parents. We identified seven differentially expressed genes and five differentially expressed noncoding RNAs. The most upregulated mRNA was stratifin (SFN) (fold change, 3.9, Benjamini–Hochberg corrected p < 0.05), and the most downregulated mRNA was goosecoid homeobox (GSC) (fold change, 3.9, Benjamini–Hochberg corrected p < 0.05). The most upregulated lncRNA was lnc-C2orf84-1 (fold change, 4.28, Benjamini–Hochberg corrected p < 0.001), and the most downregulated lncRNA was Inc-C15orf57 (fold change, −0.7, Benjamini–Hochberg corrected p < 0.05). A gene set enrichment analysis reported the enrichment of genes involved in the KRAS and E2F signaling pathways, splicing regulation and cell cycle G2/M checkpoints. Our results suggest that NSD1 is involved in cell cycle regulation and that its mutation can induce the down-expression of genes involved in tumoral and neoplastic differentiation. The results contribute to defining the role of NSD1 in fibroblasts for the prevention, diagnosis and control of SoS. Full article
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11 pages, 935 KiB  
Article
Early Salivary miRNA Expression in Extreme Low Gestational Age Newborns
by Roopa Siddaiah, Lucy Emery, Heather Stephens, Ann Donnelly, Jennifer Erkinger, Kimberly Wisecup, Steven D. Hicks, Yuka Imamura Kawasawa, Christiana Oji-Mmuo, Shaili Amatya and Patricia Silveyra
Life 2022, 12(4), 506; https://doi.org/10.3390/life12040506 - 30 Mar 2022
Cited by 1 | Viewed by 1824
Abstract
Background: MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression playing a key role in organogenesis. MiRNAs are studied in tracheal aspirates (TA) of preterm infants. However; this is difficult to obtain in infants who are not intubated. This study examines early [...] Read more.
Background: MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression playing a key role in organogenesis. MiRNAs are studied in tracheal aspirates (TA) of preterm infants. However; this is difficult to obtain in infants who are not intubated. This study examines early salivary miRNA expression as non-invasive early biomarkers in extremely low gestational age newborns (ELGANs). Methods: Saliva was collected using DNA-genotek swabs, miRNAs were analyzed using RNA seq and RT PCR arrays. Salivary miRNA expression was compared to TA using RNA seq at 3 days of age, and longitudinal changes at 28 days of age were analyzed using RT PCR arrays in ELGANs. Results: Approximately 822 ng of RNA was extracted from saliva of 7 ELGANs; Of the 757 miRNAs isolated, 161 miRNAs had significant correlation in saliva and TA at 3 days of age (r = 0.97). Longitudinal miRNA analysis showed 29 miRNAs downregulated and 394 miRNAs upregulated at 28 days compared to 3 days of age (adjusted p < 0.1). Bioinformatic analysis (Ingenuity Pathway Analysis) of differentially expressed miRNAs identified organismal injury and abnormalities and cellular development as the top physiological system development and cellular function. Conclusion: Salivary miRNA expression are source for early biomarkers of underlying pathophysiology in ELGANs. Full article
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14 pages, 1389 KiB  
Article
Coupling miR/isomiR and mRNA Expression Signatures Unveils New Molecular Layers of Endometrial Receptivity
by Maria Nikolova, Mladen Naydenov, Ilias Glogovitis, Apostol Apostolov, Merli Saare, Nageswara Boggavarapu, Andres Salumets, Vesselin Baev and Galina Yahubyan
Life 2021, 11(12), 1391; https://doi.org/10.3390/life11121391 - 11 Dec 2021
Cited by 10 | Viewed by 3198
Abstract
Embryo implantation depends on endometrial receptivity (ER). To achieve ER, the preparation of the uterine lining requires controlled priming by ovarian hormones and the expression of numerous genes in the endometrial tissue. microRNAs (miRs) have emerged as critical genetic regulators of ER in [...] Read more.
Embryo implantation depends on endometrial receptivity (ER). To achieve ER, the preparation of the uterine lining requires controlled priming by ovarian hormones and the expression of numerous genes in the endometrial tissue. microRNAs (miRs) have emerged as critical genetic regulators of ER in fertility and of the diseases that are associated with infertility. With the rapid development of next-generation sequencing technologies, it has become clear that miR genes can produce canonical miRs and variants—isomiRs. Here, we describe miR/isomiR expression dynamics across the four time points of natural chorionic gonadotropin (hCG)-administered cycles. Sequencing of the small RNAs (sRNA-seq) revealed that the most significant expression changes during the transition from the pre-receptive to the receptive phase occurred in the isomiR families of miR-125a, miR-125b, miR-10a, miR-10b, miR-449c, miR-92a, miR-92b, and miR-99a. Pairing the analysis of the differentially expressed (DE) miRs/isomiRs and their predicted DE mRNA targets uncovered 280 negatively correlating pairs. In the receptive endometrium, the 5′3′-isomiRs of miR-449c, which were among the most highly up-regulated isomiRs, showed a negative correlation with their target, transcription factor (TF) MYCN, which was down-regulated. Joint analysis of the miR/isomiR and TF expression identified several regulatory interactions. Based on these data, a regulatory TF-miR/isomiR gene-target circuit including let7g-5p and miR-345; the isomiR families of miR-10a, miR-10b, miR-92a, and miR-449c; and MYCN and TWIST1 was proposed to play a key role in the establishment of ER. Our work uncovers the complexity and dynamics of the endometrial isomiRs that can act cooperatively with miRs to control the functionally important genes that are critical to ER. Further studies of miR/isomiR expression patterns that are paired with those of their target mRNAs may provide a more in-depth picture of the endometrial pathologies that are associated with implantation failure. Full article
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Review

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12 pages, 927 KiB  
Review
Non-Coding RNAs and the Development of Chemoresistance to Docetaxel in Prostate Cancer: Regulatory Interactions and Approaches Based on Machine Learning Methods
by Elena Pudova, Anastasiya Kobelyatskaya, Marina Emelyanova, Anastasiya Snezhkina, Maria Fedorova, Vladislav Pavlov, Zulfiya Guvatova, Alexandra Dalina and Anna Kudryavtseva
Life 2023, 13(12), 2304; https://doi.org/10.3390/life13122304 - 07 Dec 2023
Viewed by 904
Abstract
Chemotherapy based on taxane-class drugs is the gold standard for treating advanced stages of various oncological diseases. However, despite the favorable response trends, most patients eventually develop resistance to this therapy. Drug resistance is the result of a combination of different events in [...] Read more.
Chemotherapy based on taxane-class drugs is the gold standard for treating advanced stages of various oncological diseases. However, despite the favorable response trends, most patients eventually develop resistance to this therapy. Drug resistance is the result of a combination of different events in the tumor cells under the influence of the drug, a comprehensive understanding of which has yet to be determined. In this review, we examine the role of the major classes of non-coding RNAs in the development of chemoresistance in the case of prostate cancer, one of the most common and socially significant types of cancer in men worldwide. We will focus on recent findings from experimental studies regarding the prognostic potential of the identified non-coding RNAs. Additionally, we will explore novel approaches based on machine learning to study these regulatory molecules, including their role in the development of drug resistance. Full article
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11 pages, 994 KiB  
Review
Hsrω and Other lncRNAs in Neuronal Functions and Disorders in Drosophila
by Anand Kumar Singh
Life 2023, 13(1), 17; https://doi.org/10.3390/life13010017 - 21 Dec 2022
Cited by 1 | Viewed by 1753
Abstract
Long noncoding RNAs (lncRNAs) have a crucial role in epigenetic, transcriptional and posttranscriptional regulation of gene expression. Many of these regulatory lncRNAs, such as MALAT1, NEAT1, HOTAIR, etc., are associated with different neurodegenerative diseases in humans. The lncRNAs produced by the hsrω gene [...] Read more.
Long noncoding RNAs (lncRNAs) have a crucial role in epigenetic, transcriptional and posttranscriptional regulation of gene expression. Many of these regulatory lncRNAs, such as MALAT1, NEAT1, HOTAIR, etc., are associated with different neurodegenerative diseases in humans. The lncRNAs produced by the hsrω gene are known to modulate neurotoxicity in polyQ and amyotrophic lateral sclerosis disease models of Drosophila. Elevated expression of hsrω lncRNAs exaggerates, while their genetic depletion through hsrω-RNAi or in an hsrω-null mutant background suppresses, the disease pathogenicity. This review discusses the possible mechanistic details and implications of the functions of hsrω lncRNAs in the modulation of neurodegenerative diseases. Full article
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30 pages, 1145 KiB  
Review
Diagnostic and Therapeutic Implications of Long Non-Coding RNAs in Leukemia
by Vladimir Gasic, Teodora Karan-Djurasevic, Djordje Pavlovic, Branka Zukic, Sonja Pavlovic and Natasa Tosic
Life 2022, 12(11), 1770; https://doi.org/10.3390/life12111770 - 02 Nov 2022
Cited by 7 | Viewed by 2140
Abstract
Leukemia is a heterogenous group of hematological malignancies categorized in four main types (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Several cytogenetic and molecular markers have become a part of routine analysis for [...] Read more.
Leukemia is a heterogenous group of hematological malignancies categorized in four main types (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Several cytogenetic and molecular markers have become a part of routine analysis for leukemia patients. These markers have been used in diagnosis, risk-stratification and targeted therapy application. Recent studies have indicated that numerous regulatory RNAs, such as long non-coding RNAs (lncRNAs), have a role in tumor initiation and progression. When it comes to leukemia, data for lncRNA involvement in its etiology, progression, diagnosis, treatment and prognosis is limited. The aim of this review is to summarize research data on lncRNAs in different types of leukemia, on their expression pattern, their role in leukemic transformation and disease progression. The usefulness of this information in the clinical setting, i.e., for diagnostic and prognostic purposes, will be emphasized. Finally, how particular lncRNAs could be used as potential targets for the application of targeted therapy will be considered. Full article
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29 pages, 1979 KiB  
Review
Modulation of Small RNA Signatures by Astrocytes on Early Neurodegeneration Stages; Implications for Biomarker Discovery
by Leonardo López-Cepeda, Juan David Castro, Andrés Felipe Aristizábal-Pachón, Yeimy González-Giraldo, Andrés Pinzón, Pedro J. Puentes-Rozo and Janneth González
Life 2022, 12(11), 1720; https://doi.org/10.3390/life12111720 - 27 Oct 2022
Cited by 1 | Viewed by 1714
Abstract
Diagnosis of neurodegenerative disease (NDD) is complex, therefore simpler, less invasive, more accurate biomarkers are needed. small non-coding RNA (sncRNA) dysregulates in NDDs and sncRNA signatures have been explored for the diagnosis of NDDs, however, the performance of previous biomarkers is still better. [...] Read more.
Diagnosis of neurodegenerative disease (NDD) is complex, therefore simpler, less invasive, more accurate biomarkers are needed. small non-coding RNA (sncRNA) dysregulates in NDDs and sncRNA signatures have been explored for the diagnosis of NDDs, however, the performance of previous biomarkers is still better. Astrocyte dysfunction promotes neurodegeneration and thus derived scnRNA signatures could provide a more precise way to identify of changes related to NDD course and pathogenesis, and it could be useful for the dissection of mechanistic insights operating in NDD. Often sncRNA are transported outside the cell by the action of secreted particles such as extracellular vesicles (EV), which protect sncRNA from degradation. Furthermore, EV associated sncRNA can cross the BBB to be found in easier to obtain peripheral samples, EVs also inherit cell-specific surface markers that can be used for the identification of Astrocyte Derived Extracellular Vesicles (ADEVs) in a peripheral sample. By the study of the sncRNA transported in ADEVs it is possible to identify astrocyte specific sncRNA signatures that could show astrocyte dysfunction in a more simpler manner than previous methods. However, sncRNA signatures in ADEV are not a copy of intracellular transcriptome and methodological aspects such as the yield of sncRNA produced in ADEV or the variable amount of ADEV captured after separation protocols must be considered. Here we review the role as signaling molecules of ADEV derived sncRNA dysregulated in conditions associated with risk of neurodegeneration, providing an explanation of why to choose ADEV for the identification of astrocyte-specific transcriptome. Finally, we discuss possible limitations of this approach and the need to improve the detection limits of sncRNA for the use of ADEV derived sncRNA signatures. Full article
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22 pages, 1100 KiB  
Review
MicroRNA: A Linking between Astrocyte Dysfunction, Mild Cognitive Impairment, and Neurodegenerative Diseases
by Angelica E. Ramírez, Natalia Gil-Jaramillo, María Alejandra Tapias, Yeimy González-Giraldo, Andrés Pinzón, Pedro J. Puentes-Rozo, Andrés Felipe Aristizábal-Pachón and Janneth González
Life 2022, 12(9), 1439; https://doi.org/10.3390/life12091439 - 16 Sep 2022
Cited by 5 | Viewed by 2656
Abstract
The importance of miRNAs in cellular processes and their dysregulation has taken significant importance in understanding different pathologies. Due to the constant increase in the prevalence of neurodegenerative diseases (ND) worldwide and their economic impact, mild cognitive impairment (MCI), considered a prodromal phase, [...] Read more.
The importance of miRNAs in cellular processes and their dysregulation has taken significant importance in understanding different pathologies. Due to the constant increase in the prevalence of neurodegenerative diseases (ND) worldwide and their economic impact, mild cognitive impairment (MCI), considered a prodromal phase, is a logical starting point to study this public health problem. Multiple studies have established the importance of miRNAs in MCI, including astrocyte regulation during stressful conditions. Additionally, the protection mechanisms exerted by astrocytes against some damage in the central nervous system (CNS) lead to astrocytic reactivation, in which a differential expression of miRNAs has been shown. Nevertheless, excessive reactivation can cause neurodegeneration, and a clear pattern defining the equilibrium point between a neuroprotective or detrimental astrocytic phenotype is unknown. Therefore, the miRNA expression has gained significant attention to understand the maintenance of brain balance and improve the diagnosis and treatment at earlier stages in the ND. Here, we provide a comprehensive review of the emerging role of miRNAs in cellular processes that contribute to the loss of cognitive function, including lipotoxicity, which can induce chronic inflammation, also considering the fundamental role of astrocytes in brain homeostasis. Full article
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17 pages, 312 KiB  
Review
microRNAs and Inflammatory Immune Response in SARS-CoV-2 Infection: A Narrative Review
by Beatrice Maranini, Giovanni Ciancio, Manuela Ferracin, Rosario Cultrera, Massimo Negrini, Silvia Sabbioni and Marcello Govoni
Life 2022, 12(2), 288; https://doi.org/10.3390/life12020288 - 15 Feb 2022
Cited by 10 | Viewed by 2566
Abstract
The current SARS-CoV-2 pandemic has emerged as an international challenge with strong medical and socioeconomic impact. The spectrum of clinical manifestations of SARS-CoV-2 is wide, covering asymptomatic or mild cases up to severe and life-threatening complications. Critical courses of SARS-CoV-2 infection are thought [...] Read more.
The current SARS-CoV-2 pandemic has emerged as an international challenge with strong medical and socioeconomic impact. The spectrum of clinical manifestations of SARS-CoV-2 is wide, covering asymptomatic or mild cases up to severe and life-threatening complications. Critical courses of SARS-CoV-2 infection are thought to be driven by the so-called “cytokine storm”, derived from an excessive immune response that induces the release of proinflammatory cytokines and chemokines. In recent years, non-coding RNAs (ncRNAs) emerged as potential diagnostic and therapeutic biomarkers in both inflammatory and infectious diseases. Therefore, the identification of SARS-CoV-2 miRNAs and host miRNAs is an important research topic, investigating the host–virus crosstalk in COVID-19 infection, trying to answer the pressing question of whether miRNA-based therapeutics can be employed to tackle SARS-CoV-2 complications. In this review, we aimed to directly address ncRNA role in SARS-CoV-2-immune system crosstalk upon COVID-19 infection, particularly focusing on inflammatory pathways and cytokine storm syndromes. Full article
22 pages, 1874 KiB  
Review
MicroRNAs as Potential Biomarkers for Exercise-Based Cancer Rehabilitation in Cancer Survivors
by Yanping Jiang, Kulsoom Ghias, Sanjeev Gupta and Ananya Gupta
Life 2021, 11(12), 1439; https://doi.org/10.3390/life11121439 - 20 Dec 2021
Cited by 2 | Viewed by 3062
Abstract
Expression and functions of microRNAs (miRNAs) have been widely investigated in cancer treatment-induced complications and as a response to physical activity, respectively, but few studies focus on the application of miRNAs as biomarkers in exercise-based cancer rehabilitation. Research has shown that certain miRNA [...] Read more.
Expression and functions of microRNAs (miRNAs) have been widely investigated in cancer treatment-induced complications and as a response to physical activity, respectively, but few studies focus on the application of miRNAs as biomarkers in exercise-based cancer rehabilitation. Research has shown that certain miRNA expression is altered substantially due to tissue damage caused by cancer treatment and chronic inflammation. MiRNAs are released from the damaged tissue and can be easily detected in blood plasma. Levels of the miRNA present in peripheral circulation can therefore be used to measure the extent of tissue damage. Moreover, damage to tissues such as cardiac and skeletal muscle significantly affects the individual’s health-related fitness, which can be determined using physiologic functional assessments. These physiologic parameters are a measure of tissue health and function and can therefore be correlated with the levels of circulating miRNAs. In this paper, we reviewed miRNAs whose expression is altered during cancer treatment and may correlate to physiological, physical, and psychological changes that significantly impact the quality of life of cancer survivors and their role in response to physical activity. We aim to identify potential miRNAs that can not only be used for monitoring changes that occur in health-related fitness during cancer treatment but can also be used to evaluate response to exercise-based rehabilitation and monitor individual progress through the rehabilitation programme. Full article
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