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Cells
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Non-coding RNAs: Epigenetic Players Implicated in Human Diseases
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Non-coding RNAs: Epigenetic Players Implicated in Human Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (1 May 2022) | Viewed by 26973

Special Issue Editor

Dr. Yujing Li

E-Mail Website
Guest Editor
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
Interests: non-coding RNA; epigenetics; genetics; neuroscience; genomics; biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Non-coding RNAs (ncRNAs) are class of RNA molecules biologically functional but not translatable into a protein. Initially, ncRNAs referred to tRNAs and rRNAs. The ncRNA field has witnessed rapid growth, identifying several new classes of ncRNAs with application of next generation sequencing technologies. The new species of ncRNAs include Small nuclear ribonucleic acid (snRNAs), Small nucleolar RNAs (snoRNAs), microRNAs (miRNAs), small interference RNAs (siRNAs), piwi-interacting RNAs (piRNAs), extracellular RNAs (exRNAs), long non-coding RNA (lncRNAs), small Cajal body-specific RNAs (scaRNAs), and circular RNAs (circRNAs).

Although the approximate number of ncRNAs encoded within the mammalian genome has not been determined precisely, the recent transcriptomic and bioinformatic studies predict the existence of a large quantity of ncRNAs in human genome.

Functionally, many of ncRNAs play essentially regulatory roles at transcriptional and post-transcriptional levels via various molecular mechanisms epigenetically, such as heterochromatin formation, DNA methylation, Histone modifications, physical interaction with chromatin-modifying proteins to recruit them to specific loci in the genome for chromatin remodeling transcriptional regulation. Particularly, the large intergenic non-coding RNAs (lincRNAs) associated with chromatin modifying complexes to target specific genomic loci to promote specific epigenetic states.

Numerous reports have documented the regulation of the ncRNAs particularly miRNAs and lncRNAs in a wide range of cellular processes. Consequently, they significantly contribute to regulation of reproduction, regeneration, growth, development and aging of the organisms particularly in mammals, and to pathogenesis of many diseases such as tumorigenesis neurological disorders, heart /kidney diseases, etc. Indeed, the emerging evidence has linked the aberrant generation of lncRNAs to down-regulation of the tumor suppressor genes and activation of the oncogenes.

This special issue will focus on the ncRNAs particularly cirRNAs and lncRNAs, while other small RNAs such as miRNAs and piRNAs are also included, due to their extensive functional characterization and emerging interest on their therapeutic potentials for stubborn diseases, such as neurological disorders and cancers.

We invite investigators in the field of ncRNAs and ncRNAs-mediated diseases such as neurodegenerative diseases, cardiac diseases, hematological diseases, and cancers, to contribute original research articles as well as review articles. Potential topics include but are not limited to the following:

  • Bioinformatic and transcriptomic tools for identification and characterization of ncRNAs particularly the unclassified ncRNAs.
  • Latest technologies for predicting the structure and function of novel cirRNAs and lncRNAs in model and non-model organisms.
  • Distribution and characterization of ncRNAs in transcriptomes among the model and non-model organisms.
  • Regulation, functions and mechanism of lncRNAs and cirRNAs in a wide range of cell processes such as the metabolic pathways.
  • Potential links between the aberrant expression levels of ncRNAs and pathogenesis of some stubborn diseases including cancer, neurological disorders, heart /kidney diseases, etc.
  • Recent developments in diagnosis of cancers, neurological diseases, and other genetic diseases with the implications of ncRNAs.
  • Targeting or delivery ncRNAs for therapy of cancer, neurological diseases, etc.
  • Epitranscriptome modifications of lncRNAs in reproduction, regeneration, growth, development, and aging.

Dr. Yujing Li
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • non-coding RNA
  • human disease
  • epigenetic marker
  • therapy
  • pathogenesis
  • transcriptome

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Related Special Issue

Published Papers (8 papers)

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Research

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21 pages, 61323 KiB  
Article
Reciprocal Regulation between lncRNA ANRIL and p15 in Steroid-Induced Glaucoma
by Peixing Wan, Siyu Huang, Yanting Luo, Caibin Deng, Jiajian Zhou, Erping Long and Yehong Zhuo
Cells 2022, 11(9), 1468; https://doi.org/10.3390/cells11091468 - 27 Apr 2022
Cited by 14 | Viewed by 3090
Abstract
Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in [...] Read more.
Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in TM dysfunction; however, whether the cellular effects of TM cells are involved in the pathogenesis of SIG remains unclear. Here, we found that the induction of cellular senescence was associated with TM dysfunction, causing SIG in cultured cells and mouse models. Especially, we established the transcriptome landscape in the TM tissue of SIG mice via microarray screening and identified ANRIL as the most differentially expressed long non-coding RNA, with a 5.4-fold change. The expression level of ANRIL was closely related to ocular manifestations (IOP elevation, cup/disc ratio, and retinal nerve fiber layer thickness). Furthermore, p15, the molecular target of ANRIL, was significantly upregulated in SIG and was correlated with ocular manifestations in an opposite direction to ANRIL. The reciprocal regulation between ANRIL and p15 was validated using luciferase reporter assay. Through depletion in cultured cells and a mouse model, ANRIL/p15 signaling was confirmed in cellular senescence via cyclin-dependent kinase activity and, subsequently, by phosphorylation of the retinoblastoma protein. ANRIL depletion imitated the SIG phenotype, most importantly IOP elevation. ANRIL depletion-induced IOP elevation in mice can be effectively suppressed by p15 depletion. Analyses of the single-cell atlas and transcriptome dynamics of human TM tissue showed that ANRIL/p15 expression is spatially enriched in human TM cells and is correlated with TM dysfunction. Moreover, ANRIL is colocalized with a GWAS risk variant (rs944800) of glaucoma, suggesting its potential role underlying genetic susceptibility of glaucoma. Together, our findings suggested that steroid treatment promoted cellular senescence, which caused TM dysfunction, IOP elevation, and irreversible vision loss. Molecular therapy targeting the ANRIL/p15 signal exerted a protective effect against steroid treatment and shed new light on glaucoma management. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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16 pages, 3699 KiB  
Article
Intranasal Administration of Agomir-let-7i Improves Cognitive Function in Mice with Traumatic Brain Injury
by Xuan-Cheng He, Jian Wang, Hong-Zhen Du, Chang-Mei Liu and Zhao-Qian Teng
Cells 2022, 11(8), 1348; https://doi.org/10.3390/cells11081348 - 15 Apr 2022
Cited by 11 | Viewed by 3128 | Correction
Abstract
Overcoming the lack of drugs for the treatment of traumatic brain injury (TBI) has long been a major challenge for the pharmaceutical industry. MiRNAs have emerged as potential targets for progress assessment and intervention against TBI. The brain-enriched miRNA let-7i has been proposed [...] Read more.
Overcoming the lack of drugs for the treatment of traumatic brain injury (TBI) has long been a major challenge for the pharmaceutical industry. MiRNAs have emerged as potential targets for progress assessment and intervention against TBI. The brain-enriched miRNA let-7i has been proposed as an ideal candidate biomarker for TBI, but its regulatory roles in brain injury remain largely unknown. Here, we find that the expression of let-7i is significantly downregulated in the early stages of a hippocampal stab wound injury. The noninvasive intranasal administration of let-7i agomir significantly improves cognitive function and suppresses neuroinflammation, glial scar formation, and neuronal apoptosis in TBI mice. Mechanically, STING is a direct downstream target of let-7i after brain injury. Furthermore, the intranasal delivery of let-7i agomir can also effectively inhibit STING and is beneficial for inflammation resolution and neuronal survival in a mouse model of pial vessel disruption stroke. Consequently, let-7i agomir is a promising candidate for clinical application as a chemically engineered oligonucleotides-based therapeutic for brain injury. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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14 pages, 3876 KiB  
Article
NAD+ Modulates the Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells via Akt Signaling Pathway
by Xiaoli Huang, Hongfeng Guo, Xuejun Cheng, Jinyu Zhang, Wenzheng Qu, Qianyun Ding, Qihang Sun, Qiang Shu and Xuekun Li
Cells 2022, 11(8), 1283; https://doi.org/10.3390/cells11081283 - 9 Apr 2022
Cited by 4 | Viewed by 2658
Abstract
Nicotinamide adenine dinucleotide hydrate (NAD+) acts as the essential component of the tricarboxylic citric acid (TCA) cycle and has important functions in diverse biological processes. However, the roles of NAD+ in regulating adult neural stem/progenitor cells (aNSPCs) remain largely unknown. Here, we show [...] Read more.
Nicotinamide adenine dinucleotide hydrate (NAD+) acts as the essential component of the tricarboxylic citric acid (TCA) cycle and has important functions in diverse biological processes. However, the roles of NAD+ in regulating adult neural stem/progenitor cells (aNSPCs) remain largely unknown. Here, we show that NAD+ exposure leads to the reduced proliferation and neuronal differentiation of aNSPCs and induces the apoptosis of aNSPCs. In addition, NAD+ exposure inhibits the morphological development of neurons. Mechanistically, RNA sequencing revealed that the transcriptome of aNSPCs is altered by NAD+ exposure. NAD+ exposure significantly decreases the expression of multiple genes related to ATP metabolism and the PI3k-Akt signaling pathway. Collectively, our findings provide some insights into the roles and mechanisms in which NAD+ regulates aNSPCs and neuronal development. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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22 pages, 6058 KiB  
Article
LncCDH5-3:3 Regulates Apoptosis, Proliferation, and Aggressiveness in Human Lung Cancer Cells
by Konrad Kwaśniak, Justyna Czarnik-Kwaśniak, Khrystyna Malysheva, Katarzyna Pogoda, Olexandr Korchynskyi, Paweł Rybojad, Bożenna Karczmarek-Borowska and Jacek Tabarkiewicz
Cells 2022, 11(3), 378; https://doi.org/10.3390/cells11030378 - 23 Jan 2022
Viewed by 2950
Abstract
(1) Lung cancer (both small cell and non-small cell) is the leading cause of new deaths associated with cancers globally in men and women. Long noncoding RNAs (lncRNAs) are associated with tumorigenesis in different types of tumors, including lung cancer. Herein, we discuss: [...] Read more.
(1) Lung cancer (both small cell and non-small cell) is the leading cause of new deaths associated with cancers globally in men and women. Long noncoding RNAs (lncRNAs) are associated with tumorigenesis in different types of tumors, including lung cancer. Herein, we discuss: (1) An examination of the expression profile of lncCDH5-3:3 in non-small cell lung cancer (NSCLC), and an evaluation of its functional role in lung cancer development and progression using in vitro models; (2) A quantitative real-time polymerase chain reaction assay that confirms lncCDH5-3:3 expression in tumor samples resected from 20 NSCLC patients, and that shows its statistically higher expression levels at stage III NSCLC, compared to stages I and II. Moreover, knockout (KO) and overexpression, as well as molecular and biochemical techniques, were used to investigate the biological functions of lncCDH5-3:3 in NSCLC cells, with a focus on the cells’ proliferation and migration; (3) The finding that lncCDH5-3:3 silencing promotes apoptosis and probably regulates the cell cycle and E-cadherin expression in adenocarcinoma cell lines. In comparison, lncCDH5-3:3 overexpression increases the expression levels of proliferation and epithelial-to-mesenchymal transition markers, such as EpCAM, Akt, and ERK1/2; however, at the same time, it also stimulates the expression of E-cadherin, which conversely inhibits the mobility capabilities of lung cancer cells; (4) The results of this study, which provide important insights into the role of lncRNAs in lung cancer. Our study shows that lncCDH5-3:3 affects important features of lung cancer cells, such as their viability and motility. The results support the idea that lncCDH5-3:3 is probably involved in the oncogenesis of NSCLC through the regulation of apoptosis and tumor cell metastasis formation. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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19 pages, 4293 KiB  
Article
Pax-5 Protein Expression Is Regulated by Transcriptional 3′UTR Editing
by Annie-Pier Beauregard, Brandon Hannay, Ehsan Gharib, Nicolas Crapoulet, Nicholas Finn, Roxann Guerrette, Amélie Ouellet and Gilles A. Robichaud
Cells 2022, 11(1), 76; https://doi.org/10.3390/cells11010076 - 28 Dec 2021
Cited by 2 | Viewed by 2758
Abstract
The Pax-5 gene encodes a transcription factor that is essential for B-cell commitment and maturation. However, Pax-5 deregulation is associated with various cancer lesions, notably hematopoietic cancers. Mechanistically, studies have characterized genetic alterations within the Pax-5 locus that result in either dominant [...] Read more.
The Pax-5 gene encodes a transcription factor that is essential for B-cell commitment and maturation. However, Pax-5 deregulation is associated with various cancer lesions, notably hematopoietic cancers. Mechanistically, studies have characterized genetic alterations within the Pax-5 locus that result in either dominant oncogenic function or haploinsufficiency-inducing mutations leading to oncogenesis. Apart from these mutations, some examples of aberrant Pax-5 expression cannot be associated with genetic alterations. In the present study, we set out to elucidate potential alterations in post-transcriptional regulation of Pax-5 expression and establish that Pax-5 transcript editing represents an important means to aberrant expression. Upon the profiling of Pax-5 mRNA in leukemic cells, we found that the 3′end of the Pax-5 transcript is submitted to alternative polyadenylation (APA) and alternative splicing events. Using rapid amplification of cDNA ends (3′RACE) from polysomal fractions, we found that Pax-5 3′ untranslated region (UTR) shortening correlates with increased ribosomal occupancy for translation. These observations were also validated using reporter gene assays with truncated 3′UTR regions cloned downstream of a luciferase gene. We also showed that Pax-5 3′UTR editing has direct repercussions on regulatory elements such as miRNAs, which in turn impact Pax-5 protein expression. More importantly, we found that advanced staging of various hematopoietic cancer lesions relates to shorter Pax-5 3′UTRs. Altogether, our findings identify novel molecular mechanisms that account for aberrant expression and function of the Pax-5 oncogene in cancer cells. These findings also present new avenues for strategic intervention in Pax-5-mediated cancers. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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15 pages, 2316 KiB  
Article
WT1-AS/IGF2BP2 Axis Is a Potential Diagnostic and Prognostic Biomarker for Lung Adenocarcinoma According to ceRNA Network Comprehensive Analysis Combined with Experiments
by Mingxi Jia, Yi Shi, Yang Xie, Wen Li, Jing Deng, Da Fu, Jie Bai, Yushui Ma, Zavuga Zuberi, Juan Li and Zheng Li
Cells 2022, 11(1), 25; https://doi.org/10.3390/cells11010025 - 23 Dec 2021
Cited by 9 | Viewed by 3168
Abstract
Lung adenocarcinoma (LUAD) is one of the most common malignancies, and there is still a lack of effective biomarkers for early detection and prognostic prediction. Here, we comprehensively analyze the characteristics of. an RNA sequencing data set of LUAD samples. In total, 395 [...] Read more.
Lung adenocarcinoma (LUAD) is one of the most common malignancies, and there is still a lack of effective biomarkers for early detection and prognostic prediction. Here, we comprehensively analyze the characteristics of. an RNA sequencing data set of LUAD samples. In total, 395 long non-coding RNAs (lncRNAs), 89 microRNAs (miRNAs), and 872 mRNAs associated with c-Myc were identified, which were differentially expressed between tumor and normal tissues. The most relevant pathway was found to be WT1-AS–miR-200a-3p–IGF2BP2 according to the rules of competitive endogenous RNA (ceRNA) regulation. WT1-AS and IGF2BP2 expression were positively correlated and increased in LUAD samples, while miR-200a-3p had relatively low expression. The high expression of WT1-AS and IGF2BP2 was associated with poor prognosis in LUAD patients, while low expression of miR-200a-3p predicted reduced survival (p < 0.05). The analysis of the multi-gene regulation model indicated that the WT1-AS (downregulation)–miR-200a-3p (upregulation)–IGF2BP2 (downregulation) pattern significantly improved the survival of LUAD patients. Finally, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were detected in LUAD cells, and the results are consistent with the bioinformatics analysis. In summary, the WT1-AS/IGF2BP2 axis is a potential prognostic biomarker in LUAD and is expected to become an effective target for diagnosis and treatment. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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Review

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18 pages, 1034 KiB  
Review
The Long Non-Coding RNA GOMAFU in Schizophrenia: Function, Disease Risk, and Beyond
by Paul M. Zakutansky and Yue Feng
Cells 2022, 11(12), 1949; https://doi.org/10.3390/cells11121949 - 17 Jun 2022
Cited by 13 | Viewed by 4454
Abstract
Neuropsychiatric diseases are among the most common brain developmental disorders, represented by schizophrenia (SZ). The complex multifactorial etiology of SZ remains poorly understood, which reflects genetic vulnerabilities and environmental risks that affect numerous genes and biological pathways. Besides the dysregulation of protein-coding genes, [...] Read more.
Neuropsychiatric diseases are among the most common brain developmental disorders, represented by schizophrenia (SZ). The complex multifactorial etiology of SZ remains poorly understood, which reflects genetic vulnerabilities and environmental risks that affect numerous genes and biological pathways. Besides the dysregulation of protein-coding genes, recent discoveries demonstrate that abnormalities associated with non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), also contribute to the pathogenesis of SZ. lncRNAs are an actively evolving family of non-coding RNAs that harbor greater than 200 nucleotides but do not encode for proteins. In general, lncRNA genes are poorly conserved. The large number of lncRNAs specifically expressed in the human brain, together with the genetic alterations and dysregulation of lncRNA genes in the SZ brain, suggests a critical role in normal cognitive function and the pathogenesis of neuropsychiatric diseases. A particular lncRNA of interest is GOMAFU, also known as MIAT and RNCR2. Growing evidence suggests the function of GOMAFU in governing neuronal development and its potential roles as a risk factor and biomarker for SZ, which will be reviewed in this article. Moreover, we discuss the potential mechanisms through which GOMAFU regulates molecular pathways, including its subcellular localization and interaction with RNA-binding proteins, and how interruption to GOMAFU pathways may contribute to the pathogenesis of SZ. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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19 pages, 947 KiB  
Review
Metastatic EMT Phenotype Is Governed by MicroRNA-200-Mediated Competing Endogenous RNA Networks
by Sara Uhan and Nina Hauptman
Cells 2022, 11(1), 73; https://doi.org/10.3390/cells11010073 - 28 Dec 2021
Cited by 8 | Viewed by 3385
Abstract
Epithelial–mesenchymal transition (EMT) is a fundamental physiologically relevant process that occurs during morphogenesis and organ development. In a pathological setting, the transition from epithelial toward mesenchymal cell phenotype is hijacked by cancer cells, allowing uncontrolled metastatic dissemination. The competing endogenous RNA (ceRNA) hypothesis [...] Read more.
Epithelial–mesenchymal transition (EMT) is a fundamental physiologically relevant process that occurs during morphogenesis and organ development. In a pathological setting, the transition from epithelial toward mesenchymal cell phenotype is hijacked by cancer cells, allowing uncontrolled metastatic dissemination. The competing endogenous RNA (ceRNA) hypothesis proposes a competitive environment resembling a large-scale regulatory network of gene expression circuits where alterations in the expression of both protein-coding and non-coding genes can make relevant contributions to EMT progression in cancer. The complex regulatory diversity is exerted through an array of diverse epigenetic factors, reaching beyond the transcriptional control that was previously thought to single-handedly govern metastatic dissemination. The present review aims to unravel the competitive relationships between naturally occurring ceRNA transcripts for the shared pool of the miRNA-200 family, which play a pivotal role in EMT related to cancer dissemination. Upon acquiring more knowledge and clinical evidence on non-genetic factors affecting neoplasia, modulation of the expression levels of diverse ceRNAs may allow for the development of novel prognostic/diagnostic markers and reveal potential targets for the disruption of cancer-related EMT. Full article
(This article belongs to the Special Issue Non-coding RNAs: Epigenetic Players Implicated in Human Diseases)
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